Indole derivatives

ABSTRACT

Compounds of the formula ##STR1## wherein n is 0, 1, or 2; X is hydrogen, chlorine, bromine or iodine; R 1  is hydrogen; R 3  is selected from hydrogen and C 1  to C 6  linear or branched alkyl; and R 2  is as defined in the specification and the pharmaceutically acceptable salts thereof are useful psychotherapeutics and are potent serotonin (5-HT 1 ) agonists and may be used in the treatment of depression, anxiety, eating disorders, obesity, drug abuse, cluster headache, migraine, pain, chronic paroxysmal hemicrania and headache associated with vascular disorders, and other disorders arising from deficient serotonergic neurotransmission. The compounds can also be used as centrally acting antihypertensives and vasodilators. A process for forming indoles by transition metal catalyzed cyclization of a dihalogenated intermediate is also disclosed.

This is a continuation-in-part of application Ser. No. 08/401,647, filedMar. 10, 1995, now abandoned, which is a continuation of applicationSer. No. 08/053,930, filed Apr. 27, 1993, now abandoned, which is acontinuation-in-part of application Ser. No. 08/039,244, filed Apr. 27,1993, now abandoned, which is a continuation-in-part of application Ser.No. 07/597,928, filed Oct. 15, 1990, now abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to indole derivatives, to processes andintermediates for their preparation, to pharmaceutical compositionscontaining them and to their medicinal use. The active compounds of thepresent invention are useful in treating migraine and other disorders.

U.S. Pat. Nos. 4,839,377 and 4,855,314 and European Patent ApplicationPublication Number 313397 refer to 5-substituted 3-aminoalkyl indoles.The compounds are said to be useful for the treatment of migraine.

British Patent Application 040279 refers to3-aminoalkyl-1H-indole-5-thioamides and carboxamides. The compounds aresaid to be useful in treating hypertension, Raymond's disease andmigraine.

European Patent Application Publication Number 303506 refers to3-poly:hydro-pyridyl-5-substituted-1H-indoles. The compounds are said tohave 5HT1-receptor agonist and vasoconstrictor activity and to be usefulin treating migraine.

European Patent Application Publication Number 354777 refers toN-piperidinyl:indolyl:ethyl-alkane sulfonamide derivatives. Thecompounds are said to have 5HT1-receptor agonist and vasoconstrictoractivity and to be useful in treating cephalic pain.

SUMMARY OF THE INVENTION

The present invention relates to compounds of the formula ##STR2##wherein n is 0, 1, or 2; X is hydrogen, chlorine, bromine, or iodine; R₁is hydrogen; R₂ is selected from hydrogen, halogen (e.g., fluorine,chlorine, bromine or iodine), cyano, --OR₄, --(CH₂)_(m) --(C═O)NR₅ R₆,--(CH₂)_(m) SO₂ NR₅ R₆, --(CH₂)_(m) --NR₇ (C═O)R₈, --(CH₂)_(m) --NR₇ SO₂R₈, --(CH₂)--S(O)_(x) R₈, --(CH₂)_(m) --NR₇ (C═O)NR₅ R₆, --(CH₂)_(m)--NR₇ (C═O)OR₉, and --CH═CH(CH₂)_(y) R₁₀ ; R₃ is selected from hydrogenand C₁ to C₆ linear and branched alkyl; R₄ is selected from hydrogen, C₁to C₆ alkyl, and aryl; R₅ and R₆ are independently selected fromhydrogen, C₁ to C₆ alkyl, aryl, and C₁ to C₃ alkyl-aryl or R₅ and R₆taken together to form a 4, 5, or 6 membered ring; R₇ and R₈ areindependently selected from hydrogen, C₁ to C₆ alkyl, aryl, and C₁ to C₃alkyl-aryl; R₉ is selected from hydrogen, C₁ to C₆ alkyl, aryl, and C₁to C₃ alkyl-aryl; R₁₀ is selected from --(C═O)NR₅ R₆ and --SO₂ NR₅ R₆,wherein R₅ and R₆ are defined as above, and --NR₇ (C═O)R₈, --NR₇ SO₂ R₈,--NR₇ (C═O)NR₅ R₆, --S(O)_(x) R₈ and --NR₇ (C═O)OR₉, wherein R₇, R₈, andR₉ are as defined above; m is 0, 1, 2, or 3; y is 0, 1, or 2; x is 1 or2; and the above aryl groups and the aryl moieties of the abovealkylaryl groups are independently selected from phenyl and substitutedphenyl, wherein said substituted phenyl may be substituted with one tothree groups selected from C₁ to C₄ alkyl, halogen (e.g., fluorine,chlorine, bromine or iodine), hydroxy, cyano, carboxamido, nitro and C₁to C₄ alkoxy, with the proviso that when R₂ is hydrogen or --OR₄ and R₄is hydrogen, n is 0 or 1, and the pharmaceutically acceptable saltsthereof. These compounds are useful in treating migraine and-otherdisorders. Compounds of the formula I wherein R₂ is --CH═CH(CH₂)R₁₀ andcompounds of formula I where X is chlorine, bromine, or iodine are alsouseful as intermediates for preparing other compounds of the formula I.

The compounds of the invention include all optical isomers of formula I(e.g., R and S enantiomers) and their racemic mixtures. The Renantiomers at the designated chiral site in formula I are preferred.

Unless otherwise indicated, the alkyl groups referred to herein, as wellas the alkyl moieties of other groups referred to herein (e.g. alkoxy),may be linear or branched, and they may also be cyclic (e.g.,cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) or be linear orbranched and contain cyclic moieties.

Preferred compounds of the invention are compounds of the formula Iwherein R₁ is hydrogen; R₂ is --(CH₂)_(m) --SO₂ NHR₅, --(CH₂)_(m)--NHSO₂ R₈, --(CH₂)_(m) --SO₂ R₈, --(CH₂)_(m) --(C═O)NHR₅, or--(CH₂)_(m) --NH(C═O)R₈ ; R₃ is hydrogen or methyl; and m, R₅ and R₈ areas defined above and the pharmaceutically acceptable salts thereof. Ofthe foregoing preferred compounds, the R enantiomers at the designatedchiral site in formula I are more preferred.

The following compounds are preferred:

(R)-5-methoxy-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole;

(R)-5-bromo-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole;

(R)-5-(2-ethylsulfonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole;

(R)-5-(2-methylaminosulfonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole;

(R)-5-(2-methylaminosulfonylethyl)-3-(pyrrolidin-2-ylmethyl)-1H-indole;

(R)-5-carboxamido-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole;

(R)-5-(2-methylsulfonylethyl)-3-(N-methylpyrrolidin-2-yl-methyl)-1H-indole;

(R)-5-(2-aminosulphonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole;

(R)-5-(2-aminosulphonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole;

(R)-5-(2-N,N-dimethylaminosulphonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole;

(R)-5-(2-phenylsulphonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole[also known as

(R)-5-(2-benzenesulphonylethyl)-3-(N-methyl-pyrrolidin-2-ylmethyl)-1H-indole];

(R)-5-(2-phenylsulphonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indolehemisuccinate [also known as(R)-5-(2-benzenesulphonylethyl)-3-(N-methyl-pyrrolidin-2-ylmethyl)-1H-indolehemisuccinate];

(R)-5-(2-phenylsulphonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indolehydrobromide;

(R)-5-(2-ethylsulphonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indolehemisuccinate;

(R)-5-(3-benzenecarbonylaminoprop-1-enyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole;

(R)-5-(2-(4-methylphenylsulphonyl)ethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole;

(R)-5-(3-methylsulphonylaminoprop-1-enyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole;

(R)-5-(2-ethylsulphonylethyl)-3-(N-2-propylpyrrolidin-2-ylmethyl)-1H-indole;

(R)-5-(2-ethylsulphonylethyl)-3-(pyrrolidin-2-ylmethyl)-1H-indole;

(R)-5-(2-(4-methylphenylsulphonyl)ethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole;

(R)-5-(2-methylsulfonamidoethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole;

(R)-5-(2-methylsulfonamidomethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole;

(R)-5-(methylaminosulfonylmethyl)-3-(N-methyl-pyrrolidin-2-ylmethyl)-1H-indole;

(R)-5-(methylaminosulfonylmethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indolefumarate;

(R)-5-(methylaminosulfonylmethyl)-3-(pyrrolidin-2-ylmethyl)-1H-indole;

(R)-5-(aminosulphonylmethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole;

(R)-5-aminosulfonyl-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole; and

(R)-7-Bromo-5-(methylaminosulfonylmethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole.

The following compounds are particularly preferred:

(R)-5-(2-phenylsulphonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole;

(R)-5-(methylaminosulfonylmethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole;

(R)-5-(aminosulfonylmethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole;

(R)-5-(methylaminosulfonylmethyl)-3-(pyrrolidin-2-ylmethyl)-1H-indole;

(R)-5-(methylaminosulfonylmethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indolefumarate; and

(R)-5-(2-phenylsulphonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indolehydrobromide.

The following are other specific compounds of the present invention:

(R)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole;

(R)-5-fluoro-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole;

(R)-5-acetylamino-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole;

(R)-5-benzyloxycarbonylamino-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole;

(R)-5-(2-aminocarbonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole;

(R)-5-aminocarbonylmethyl-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole;

(R)-5-methylsulfonamido-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole; and

(R)-5-(aminosulfonylmethyl)-3-(pyrrolidin-2-ylmethyl)-1H-indole.

The present invention also relates to a pharmaceutical composition fortreating a condition selected from hypertension, depression, anxiety,eating disorders, obesity, drug abuse, cluster headache, migraine, pain,and chronic paroxysmal hemicrania and headache associated with vasculardisorders comprising an amount of a compound of the formula I or apharmaceutically acceptable salt thereof effective in treating suchcondition and a pharmaceutically acceptable carrier.

The present invention also relates to a pharmaceutical composition fortreating disorders arising from deficient serotonergic neurotransmission(e.g., depression, anxiety, eating disorders, obesity, drug abuse,cluster headache, migraine, pain, and chronic paroxysmal hemicrania andheadache associated with vascular disorders) comprising an amount of acompound of the formula I or a pharmaceutically acceptable salt thereofeffective in treating such condition and a pharmaceutically acceptablecarrier.

The present invention also relates to a method for treating a conditionselected from hypertension, depression, anxiety, eating disorders,obesity, drug abuse, cluster headache, migraine, pain and chronicparoxysmal hemicrania and headache associated with vascular disorderscomprising administering to a mammal (e.g., a human) requiring suchtreatment an amount of a compound of the formula I or a pharmaceuticallyacceptable salt thereof effective in treating such condition.

The present invention also relates to a method for treating disordersarising from deficient serotonergic neurotransmission (e.g., depression,anxiety, eating disorders, obesity, drug abuse, cluster headache,migraine, pain and chronic paroxysmal hemicrania and headache associatedwith vascular disorders) comprising administering to a mammal (e.g., ahuman) requiring such treatment an amount of a compound of the formula Ior a pharmaceutically acceptable salt thereof effective in treating suchcondition.

The contemplated range for both pharmaceutical compositions and methodsof use of the compound(R)-5-(methylaminosulfonylmethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indoleis from 0.1 μg to 200 mg.

The contemplated range for both pharmaceutical compositions and methodsof use of the compound(R)-5-(aminosulfonylmethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indoleis from 0.1 μg to 200 mg.

The contemplated range for both pharmaceutical compositions and methodsof use of the compound(R)-5-(methylaminosulfonylmethyl)-3-(pyrrolidin-2-ylmethyl)-1H-indole isfrom 0.01 μg to 200 mg.

The present invention also relates to a compound of the formula ##STR3##wherein X is hydrogen, bromine, chlorine, or iodine; W is --CO₂ R₁₁ orR₃ ; Q is CH₂ or C═O; n, R₁, R₂ and R₃ are as defined for formula I; andR₁₁ is selected from C₁ to C₆ alkyl, benzyl and aryl, wherein aryl is asdefined above, with the proviso that when W is R₃, Q is C═O, and withthe proviso that when X is bromine, chlorine, or iodine, W is --CCO₂ R₁₁and Q is CH₂. The compounds of formula V are useful as intermediates inpreparing compounds of the formula I.

Accordingly, one group of the foregoing intermediates comprisescompounds of the formula ##STR4## wherein n, R₁, R₂ and R₁₁ are asdefined above and a second group of the foregoing intermediatescomprises compounds of the formula ##STR5## wherein n, R₁, R₃ and R₁₀are as defined above.

The present invention also relates to a process for preparing a compoundof the formula ##STR6## wherein X is chlorine, bromine, or iodine; A isa first suitable nitrogen protecting group; R₁₅ is hydrogen, halogen,cyano, --OR₁₆, --(CH₂)_(m) --(C═O)NR₁₇ R₁₈, --(CH₂)_(m) --SO₂ NR₁₇ R₁₈,--(CH₂)_(m) --NR₁₉ (C═O)R₂₀, --(CH₂)_(m) --NR₁₉ SO₂ R₂₀, --(CH₂)_(m)--S(O)_(x) R₂₀, --(CH₂)_(m) --NR₁₉ (C═O)NR₁₇ R₁₈, --(CH₂)_(m) --NR₁₉(C═O)OR₂₁, --CH═CH(CH₂)_(y) R₂₂, --(CH₂)_(m) --T, and a substituent ofthe formula ##STR7## B represents a direct bond, C₁ -C₄ alkyl, or C₁ -C₄alkenyl; D, E, G, and J are each independently oxygen, sulfur, nitrogenor carbon, provided that at least one of D, E, G, and J is nitrogen;R₂₈, R₂₉, R₃₀, and R₃₁ are each independently hydrogen, C₁ -C₆ alkyl,aryl, C₁ -C₃ alkylaryl, C₁ -C₃ alkylheteroaryl, halogen, cyano,trifluoromethyl, nitro, --OR₃₂, --NR₃₂ R₃₃, --(CH₂)_(m) OR₃₂, --SR₃₂,--SO₂ NR₃₂ R₃₃, --NR₃₂ SO₂ R₃₃, --NR₃₂ CO₂ R₃₃, --CONR₃₂ R₃₃, or --CO₂R₃₂ ; one of R₂₈ and R₂₉, R₂₉ and R₃₀, or R₃₀ and R₃₁ may be takentogether to form a five- to seven-membered alkyl ring, a six-memberedaryl ring, a five- to seven-membered heteroalkyl ring having 1heteroatom of N, O, or S, or a five- to six-membered heteroaryl ringhaving 1 or 2 heteroatoms of N, O, or S; R₃₂ and R₃₃ are eachindependently hydrogen, C₁ to C₆ alkyl, --(CH₂)_(q) R₃₄, C₁ to C₃alkylaryl, or aryl; R₃₂ and R₃₃ may be taken together to form a C₄ -C₇alkyl ring; R₃₄ is cyano, trifluoromethyl, or C₁ -C₄ alkoxy; R₁₆ ishydrogen, C₁ to C₆ alkyl, or aryl; T is ##STR8## M and Q are eachindependently oxygen or sulfur; Z is --O--, --S--, --NH, or --CH₂ ; R₃₅and R₃₆ are each independently hydrogen, C₁ to C₆ alkyl, aryl, C₁ to C₃alkylaryl, or C, to C₃ alkylheteroaryl; R₂₂ is --(C═O)NR₂₃ R₂₄, --SO₂NR₂₃ R₂₄, --NR₂₅ (C═O)R₂₆, --NR₂₅ SO₂ R₂₆, --NR₂₅ (C═O)NR₂₃ R₂₄,--S(O)_(x) R₂₆ or --NR₇ (C═O)OR₂₇ ; R₁₇, R₁₈, R₂₃, and R₂₄ are eachindependently hydrogen, C₁ to C₆ alkyl, aryl, or C₁ to C₃ alkyl-aryl, orR₁₇ and R₁₈ or R₂₃ and R₂₄ maybe taken together to form a four- tosix-membered ring; R₁₉, R₂₀, R₂₁, R₂₅, R₂₆, and R₂₇ are eachindependently hydrogen, C₁ to C₆ alkyl, aryl, or C₁ to C₃ alkyl-aryl; yis 0, 1, or 2; x is 1 or 2; m is 0, 1, 2, or 3; n is 0, 1 or 2; q is 1,2, or 3; and the above aryl groups and the aryl moieties of the abovealkylaryl groups are independently selected from phenyl and substitutedphenyl, wherein said substituted phenyl may be substituted with one tothree groups selected from C₁ to C₄ alkyl, halogen, hydroxy, cyano,carboxamido, nitro, and C₁ to C₄ alkoxy,

comprising, performing a transition metal catalyzed cyclization on acompound of the formula ##STR9## wherein R₁₅, A, and X are as definedabove and V is a second suitable nitrogen protecting group.

The process is preferable used where X is bromine.

The compounds of formula XVI are useful in preparing the compounds offormula I, as well as preparing the 5-HT_(1D) agonists disclosed inInternational Application Nos. WO 93/18032(published Sep. 16, 1993) andWO 93/20073 (published Oct. 14, 1993).

DETAILED DESCRIPTION OF THE INVENTION

Compounds of formula I are prepared by hydride reduction of a compoundof the formula ##STR10## wherein R₁, R₂, n and R₁₁ are as defined abovewith a hydride reducing agent in an inert solvent. Suitable hydridereducing agents include lithium aluminum hydride, diborane, lithiumborohydride and sodium borohydride. The preferred reagent is lithiumaluminum hydride. Suitable solvents include ethers, such as diethylether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane. Thepreferred solvent is tetrahydrofuran. The reaction is conducted at atemperature of about 30° C. to about 100° C., preferably about 65° C. toabout 70° C.

Compounds of formula I are also prepared by catalytic reduction of acompound of the formula ##STR11## wherein R₁, R₃, n and R₁₀ are asdefined above under an atmosphere of hydrogen, preferably at a pressureof about 1 to about 3 atmospheres, or using a hydrogen source such asammonium formate or formic acid in an inert solvent. Suitable catalystsinclude palladium on carbon, Raney nickel, platinum oxide, rhodium, andruthenium. The preferred catalyst is palladium on carbon. Suitablesolvents include C₁ to C₆ alcohols, N,N-dimethylformamide, ethylacetate, acetonitrile, and acetone. The preferred solvents are ethanoland acetone. The reaction is conducted at a temperature of about 0° C.to about 60° C., most preferably at about 25° C.

Compounds of formula I are also prepared by alkylation of compounds offormula I where R₃ ═H and R₂ and R₁, are as defined for formula I withalkyl halides in the presence of a base in an inert solvent. Suitablealkyl halides include alkyl halides of the formula R³ -Halide where thehalide is chloride, bromide and iodide. The preferred halide is iodide,or bromide in the presence of a suitable iodide source such as sodiumiodide. Suitable bases include tertiary amines and inorganic bases. Thepreferred base is sodium carbonate. Suitable solvents includeN,N-dimethylacetamide, N,N-dimethylformamide, dimethoxyethane,tetrahydrofuran, dichloromethane, and acetonitrile. The preferredsolvent is N,N-dimethylacetamide. The reaction is conducted at atemperature of about 0° C. to about 150° C., preferably at about 120° C.

Compounds of formula I are also prepared by alkylation of compounds offormula I where R₃ ═H and R₂ and R₁ are as defined from formula I, withaldehydes and ketones in the presence of a hydride source. Suitablealdehydes are of the formula R₃₇ CHO where R₃₇ is C₁ to C₅ alkyl. Thepreferred aldehyde is formaldehyde. Suitable ketones are of the formulaR₃₈ (C═O)R₃₉ where R₃₈ and R₃₉ are each independently C₁ to C₅ alkylprovided that the total number of carbons in both R₃₈ and R₃₉ is at mostfive. Suitable hydride sources include formic acid derivatives,phosphorous acids, and alkali metal borohydrides. The preferred hydridesource are formic acid, sodium triacetoxyborohydride, sodiumcyanoborohydride and the monosodium salt of phosphorous acid, with themore preferred hydride source being the monosodium salt of phosphorousacid (H. Loibner, Tet. Lett. (1984) p. 2535). The reaction is usuallyconducted at a temperature of from about ambient temperature (about 27°C.) to about reflux temperature, preferably 60° C. (with preferredsolvent of tetrahydrofuran (hereinafter referred to as THF)). Suitablesolvents in which the reaction can be run include aqueous THF, aqueousdioxane, water plus one of the lower alcohols (e.g., methanol orethanol), ethers, esters (ethyl acetate), or halogenated hydrocarbons(dichloromethane or chloroform), or acetonitrile, preferably aqueousTHF.

As an alternative to the process in the previous paragraph, compounds offormula I can be prepared via a reductive amination using an aldehyde orketone, of the formulae described in the previous paragraph, along witha transition metal catalyst, and a hydrogen source in an inert solvent.Suitable catalysts include palladium on carbon, Raney nickel, platinumoxide, and palladium hydroxide on carbon. The preferred catalyst ispalladium hydroxide on carbon. Suitable hydrogen sources includehydrogen gas, ammonium formate, and formic acid. Hydrogen gas at apressure of from about one to about three atmospheres is the preferredhydrogen source. Three atmospheres of hydrogen gas is the preferredpressure. Suitable solvents include C₁ to C₄ alcohols, acetonitrile,N,N-dimethylformamide, and N-methylpyrrolidine. Ethanol is the preferredsolvent. The reaction is usually conducted at a temperature of fromabout 25° C. to about 100° C., preferably about 25° C. to about 50° C.

The compounds of formula II can be prepared by reacting a magnesium saltof an indole derivative of the formula ##STR12## wherein R₁ and R₂ aredefined above, with the acid chloride of an N--CO₂ R₁₁ -proline, N--CO₂R₁₁ -azetidine-2-carboxylic acid, or N--CO₂ R₁₁ -pipecolinic acid (R, S,or racemate), wherein R₁₁ is defined as above, in a ratio of from about1:1 to about 2:1, preferably 2:1 (indole magnesium salt:acid chloridecompound). The indole magnesium salt is first prepared from the reactionof an indole of formula IV with an alkyl or aryl magnesium halide,preferably ethylmagnesium bromide. The reaction is generally conductedin an inert solvent at a temperature between about -30° C. and about 65°C., preferably at about 25° C.. Suitable solvents include diethyl ether,tetrahydrofuran, and other alkyl ethers and dichloromethane withtoluene. The preferred solvents are diethyl ether and dichloromethanewith toluene. The acid chloride of proline, azetidine-2-carboxylic acid,or pipecolinic acid is prepared in a separate reaction vessel byreaction of the N--CO₂ R₁₁ -proline, N--CO₂ R₁₁ -azetidine-2-carboxylicacid, or N--CO₂ R₁₁ -pipecolinic acid (R, S, or racemate), with oxalylchloride in methylene chloride at about -10° C. to about 25° C. (Helv.Chim. Acta, 1920 (1976)). Suitable solvents include diethyl ether,tetrahydrofuran, other alkyl ethers, and methylene chloride. Theproline, azetidine-2-carboxylic acid, or pipecolinic acid isN-substituted with a protecting group to avoid reaction of the nitrogenwith the acid chloride when it is formed. Suitable protecting groups aresubstituted-aryl or substituted-alkyl carbamates (e.g.benzyloxycarbonyl). Preferably, a solution of the N--CO₂ R₁₁ -prolineacid chloride in an inert solvent (e.g., diethyl ether) is added slowlyto the solution of the magnesium salt of an indole of formula IV at atemperature of about -30° C. to about 50° C., preferably at about 25° C.

The compounds of formula III can be prepared by reacting a compound offormula ##STR13## where in R₁, R₃ and n are defined as above and X ischlorine, bromine or iodine (preferably bromine), with a compoundcontaining a vinyl group (e.g. ethyl vinyl sulfone orN-methylvinylsulfonamide) in the presence of a palladium catalyst, atriarylphosphine and a base in an inert solvent. Suitable catalystsinclude palladium (II) salts, preferably palladium (II) acetate.Suitable solvents include acetonitrile, N,N-dimethylformamide,tetrahydrofuran and N,N-dimethylformamide with 1,2-dimethoxyethane. Thepreferred solvents are acetonitrile and N,N-dimethylformamide. Thepreferred triarylphosphine is tri-o-tolylphosphine. Suitable basesinclude trisubstituted amines. The preferred base is triethylamine. Thereaction is conducted at a temperature of about 25° C. to 150° C., mostpreferably at about 80° C.

The reaction in the previous paragraph can also be preformed on thecompound of formula V where R₁ is a suitable nitrogen protecting group,using those known in the art. The preferred groups are electronwithdrawing groups, preferably acetyl. Once the above reaction iscomplete, the corresponding compound of formula III with theaforementioned protecting group can be isolated by crystallization. Theprotecting group is then removed using methods known in the art toresult in the compound of formula III defined previously on page 11. Theprocedure described in this paragraph differs from that described in theprevious paragraph in that this procedural step eliminates the need touse a column to isolate the desired compound.

Compounds of formula I and intermediates to compounds of formula I canbe prepared by hydride reduction of a compound of the formula ##STR14##wherein R₂, n, and R₁₁ are as defined above with a hydride reducingagent in an inert solvent. Suitable hydride reducing agents includelithium aluminum hydride, diborane, lithium borohydride, and sodiumamide. The preferred reagent is lithium aluminum hydride. Suitablesolvents include ethers, such as diethyl ether, tetrahydrofuran,1,4-dioxane and 1,2-dimethoxyethane. The preferred solvent istetrahydrofuran. The reduction is conducted at a temperature of about30° C. to about 100° C., preferably about 65° C. to about 70° C.

Compounds of formula I and intermediates to compounds of formula I canalso be prepared by catalytic reduction of a compound of the formula##STR15## wherein R₂, n, and R₁₁ are as defined above under anatmosphere of hydrogen, preferably at a pressure of about 1 to 3atmospheres, or using a hydrogen source such as ammonium formate offormic acid in an inert solvent. Suitable catalysts include palladium oncarbon, Raney nickel, and platinum oxide. The preferred catalyst ispalladium on carbon. Suitable solvents include C₁ to C₆ alcohols,N,N-dimethylformamide, ethyl acetate, and acetonitrile. The preferredsolvent is ethanol. The reaction is conducted at a temperature of about0° C. to about 60° C., preferably at about 25° C.

Compounds of formula VI can be prepared by the transition metalcatalyzed cyclization of a compound of the formula ##STR16## wherein R₂,n, and R₁₁ are as defined above, and X is chlorine, bromine, or iodine(preferably bromine or iodine), and R₁₂ is --OR₁₁ as defined above oralkyl, aryl, or trifluoromethyl (preferably trifluoromethyl) in asuitable inert solvent with a phase transfer catalyst and a base.Suitable catalysts include palladium salts such as palladium (II)acetate or palladium (II) chloride (preferably palladium acetate) andrhodium salts, such as tris(triphenyl)rhodium (I) chloride. Suitablesolvents include N,N-dimethylformamide, N,N-dimethylformamide withdimethoxyethane, acetonitrile, and N-methylpyrrolidine. The preferredsolvents are N,N-dimethylformamide and N,N-dimethylformamide withdimethoxyethane. Suitable phase transfer catalysts includetetraalkylammonium halides, preferably tetra-n-butylammonium chloride.Suitable bases include tertiary amines, sodium hydrogen carbonate, andsodium carbonate. The,preferred base is triethylamine. The reaction isconducted at a temperature of about 80° C. to about 180° C., preferablyabout 150° C. to 160° C.

Compounds of formula VI can also be prepared by hydride reduction of acompound of the formula ##STR17## wherein R₂, n, and R₁₁ are as definedabove with a hydride reducing agent in an inert solvent. Suitablehydride reducing agents include lithium borohydride, sodium borohydride,and sodium cyanoborohydride. The preferred reagent is lithiumborohydride. Suitable solvents include ethers, such as diethyl ether,tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane. The preferredsolvent is tetrahydrofuran. The reduction is conducted at a temperatureof about 30° C. to about 100° C., preferably about 65° C. to about 70°C.

Compounds of formula VII can be prepared by the Mitsunobu couplingreaction of compounds of formulas ##STR18## wherein R₂, n, R₁₁, and R₁₂are as defined above using a phosphine and an azodicarboxylate in asuitable solvent. Suitable phosphines include trialkylphosphines andtriarylphosphines, preferably triphenylphosphine. Suitableazodicarboxylates include dialkyl azodicarboxylates, preferably diethylazodicarboxylate. Suitable solvents include methylene chloride, ethers,including tetrahydrofuran, diethyl ether, and 1,4-dioxane,N-N-dimethylformamide and acetonitrile. The preferred solvent istetrahydrofuran. The reaction is conducted at a temperature of about 0°C. to about 65° C., most preferably at about 25° C.

Compounds of formula VIII, if not available commercially, can beprepared by reacting a compound of formula X ##STR19## wherein R₂ and Xare as defined above with the acid chloride or the symmetrical anhydrideof R₁₂ CO₂ H in a suitable solvent with an suitable base. The preferredacid chloride or anhydride is trifluoroacetic anhydride. Suitablesolvents include ethers, including tetrahydrofuran, diethyl ether and1,4-dioxane, methylene chloride, and chloroform. The preferred solventis methylene chloride. Suitable bases include triethylamine, pyridine,and sodium hydrogen carbonate. The preferred base is pyridine. Thereaction is conducted at a temperature of about 0° C. to about 65° C.,preferably at about 25° C.

Compounds of formula X, if not available commercially, can be preparedby reacting a compound of formula XI ##STR20## wherein R₂ is as definedabove with either chlorine, bromine, or iodine in a suitable solventwith a suitable base. Reaction with bromine is preferred. Suitablesolvents include C₁ -C₆ alcohols, methylene chloride, methanol withmethylene chloride, chloroform, or carbon tetrachloride. The preferredsolvents are methanol and methanol with methylene chloride. Suitablebases include triethylamine, pyridine, sodium carbonate, and sodiumhydrogen carbonate. The preferred base is sodium hydrogen carbonate. Thereaction is conducted at a temperature of about 0° C. to about 65° C.,preferably at about 25° C.

Compounds of the formula IX can be prepared from hydride reduction of acompound of formula XII ##STR21## wherein R₁₁ is defined as above andR₁₃ is C₁ -C₆ alkyl, aryl, or alkylaryl with a hydride reducing agent inan inert solvent. Suitable hydride reducing agents include lithiumaluminum hydride, lithium borohydride, sodium borohydride, anddiisobutylaluminum hydride. The preferred reagent is diisobutylaluminumhydride. Suitable solvents include ethers, such as diethyl ether,tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane. The preferredsolvent is tetrahydrofuran. The reduction is conducted at a temperatureof about -100° C. to about 0° C., preferably at about -80° C. to about-60° C., more preferably at about -70° C. to about -60° C.

Compounds of the formula XII can be prepared from the Wittig reaction ina suitable solvent involving compounds of the formulas ##STR22## whereinR₁₁ and R₁₃ are defined as above. Suitable solvents include ethers suchas diethyl ether, tetrahydrofuran, and 1,4-dioxane. Tetrahydrofuran isthe preferred solvent. The reaction is conducted by adding the reagentsat a temperature of about -78° C. to about 30° C., preferably either atabout -78° C. to minimize possible racemization, or at about roomtemperature should racemization not be problematic. The reagent solutionis then warmed to room temperature, if necessary, and then heated to thereflux temperature of the solvent (67° C. reflux temperature ofpreferred solvent THF).

Compounds of the formula XIII can be prepared as outlined in S. Kiyooka,et al., J. Org. Chem., 5409 (1989) and Y. Hamada, et al., Chem. Pharm.Bull., 1921 (1982).

Compounds of the formula XIV are either commercially available or can beprepared as outlined in L. Fieser and M. Fieser, Reagents for OrganicSynthesis, John Wiley and Sons, New York, Vol. 1, p. 112 (1967).

Compounds of formula I (which include compounds claimed in the presentapplication as well as in international published application nos. WO93/18032 and WO 93/20073) are also prepared by catalytic reduction of acompound of the formula ##STR23## wherein R³ is as defined above or is asubstituent of the formula --CO₂ --R_(q), R_(q) is benzyl or substitutedbenzyl, and where R¹, R² and n are as defined above and X is chlorine,bromine or iodine (preferably bromine or iodine) under an atmosphere ofhydrogen, preferably at a pressure of about 1 to 4 atmospheres, or usinga hydrogen source such as ammonium formate or formic acid in an inertsolvent. Suitable catalysts include 20% palladium (II) hydroxide oncarbon, palladium on carbon, Raney nickel, platinum oxide, rhodium andruthenium. The preferred catalyst is 20% palladium (II) hydroxide oncarbon. Suitable solvents include C₁ to C₆ alcohols,N,N-dimethylformamide, ethyl acetate and acetonitrile. The preferredsolvent is ethanol. The reaction is generally conducted at a temperatureof about 0° C. to about 60° C., most preferably at about 25° C.

Compounds of formula XV are prepared by hydride reduction of a compoundof the formula ##STR24## wherein R₂, n and A are as defined above and Xis chlorine, bromine or iodine (preferably bromine or iodine) with ahydride reducing agent in an inert solvent, as described for the hydridereduction of compounds of formula VI on page 15 and 16 of thespecification. Examples of A include t-butoxycarbonyl(BOC) andbenzyloxycarbonyl(CBZ), preferably CBZ (See T. W. Green, ProtectingGroups in Organic Synthesis, John Wiley & Sons (1981) pp 218-287). Aside product of this reaction can be a compound of formula I where X ishydrogen and R₃ is methyl.

Compounds of formula XVI can be prepared by the transition metalcatalyzed cyclization of a compound of the formula ##STR25## wherein R₂,n, A, and V are as defined above, and X is chlorine, bromine or iodine(preferably bromine or iodine) and R₁₂ is --OR₁₁ as defined above oralkyl, aryl, or trifluoromethyl (preferably trifluoromethyl) in asuitable inert solvent with a phase transfer catalyst, a base and asuitable transition metal catalyst, as described for the transitionmetal catalyzed cyclization of a compound of formula VII on pages 16 to17 of the specification. Examples of V include t-butoxycarbonyl(BOC),benzyloxycarbonyl(CBZ), and trifluoroacetyl, preferablytrifluoromethylacetyl (See T. W. Green, Protecting Groups in OrganicSynthesis, John Wiley & Sons (1981) pp 218-287).

Compounds of formula XVII, can be prepared by the Mitsunobu couplingreaction of compounds of formulae ##STR26## wherein R₂, n, R₁₁, R₁₂ andX are as defined above using a phosphine and an azodicarboxylate in asuitable solvent, as described for the Mitsunobu coupling reaction ofcompounds of formulas VIII and IX on pages 17 and 18 of thespecification.

Compounds of formula XVIII, if not available commercially, can beprepared by reacting a compound of formula ##STR27## wherein R₂ and Xare as defined above with the acid chloride or the symmetricalcarboxylic anhydride of the formula V--O--V, where V is as definedabove, in a suitable solvent with a suitable base, as described for thepreparation of compounds of formula VIII on pages 18 and 19 of thespecification.

Compounds of formula XX, if not available commercially, can be preparedby reacting a compound of formula ##STR28## wherein R₂ is as definedabove with either chlorine, bromine or iodine in a suitable solvent witha suitable base, as described for the preparation of compounds offormula X on page 17 of the specification, except that two equivalentsof halogen are required.

Compounds of the formula XXI, if not commercially available, can beprepared as described for the preparation of the compounds of formula XIon page 19 of the specification.

Compounds of formula I are also prepared by reaction of a compound offormula ##STR29## wherein R₁, R₃, R₅, m and n are as defined above andR₁₄ is a suitable sulfonamide N protecting group such as t-butyl orbenzyl, preferably t-butyl. Suitable conditions for removing such aprotecting group are known in the art, for example, when R₁₄ is t-butyl,treatment with a strong acid such as trifluoroacetic acid orhydrochloric acid. In the case of trifluoroacetic acid, the acid can beused neat, or in a suitable inert solvent such as diethyl ether ordichloromethane.

Alternatively, protection of the indole ring in situ can be achieved byinitial treatment with an indole-N-1 acylating agent, such as aceticanhydride or acetyl chloride, using procedures known in the art. Forexample where acetic anhydride is used, the acylating agent can be usedneat, or in a suitable inert solvent, such as diethyl ether ordichloromethane. This is followed by removal of the sulfonamide Nprotecting group, R₁₄, as outlined above and then hydrolytic removal ofthe indole-1-acyl protecting group using a suitable hydrolytic agentknown in the art, such as a hydroxide or carbonate salt, preferablypotassium carbonate in a suitable solvent. Suitable solvents include C₁to C₆ alcohols, preferably methanol or ethanol. The above process can becarried out as a one pot procedure to afford compounds of formula Idirectly from compounds of formula XXII.

Unless indicated otherwise, the pressure of each of the above reactionsis not critical. Generally, the reactions will be conducted at apressure of about one to about three atmospheres, preferably at ambientpressure (about one atmosphere).

The compounds of the formula I which are basic in nature are capable offorming a wide variety of different salts with various inorganic andorganic acids. Although such salts must be pharmaceutically acceptablefor administration to animals, it is often desirable in practice toinitially isolate a compound of the formula I from the reaction mixtureas a pharmaceutically unacceptable salt and then simply convert thelatter back to the free base compound by treatment with an alkalinereagent, and subsequently convert the free base to a pharmaceuticallyacceptable acid addition salt. The acid addition salts of the basecompounds of this invention are readily prepared by treating the basecompound with a substantially equivalent amount of the chosen mineral ororganic acid in an aqueous solvent medium or in a suitable organicsolvent such as methanol or ethanol. If necessary, upon carefulevaporation of the solvent, the desired solid salt is obtained.

The acids which are used to prepare the pharmaceutically acceptable acidaddition salts of the base compounds of this invention are those whichform non-toxic acid addition salts, i.e., salts containingpharmacologically acceptable anions, such as hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate oracid phosphate, acetate, lactate, citrate or acid citrate, tartrate orbitartrate, succinate, maleate, fumarate, gluconate, saccharate,benzoate, methanesulfonate and pamoate [i.e.,1,1'-methylene-bis-(2-hydroxy-3-naphthoate)] salts.

Those compounds of the formula I which are also acidic in nature, e.g.,where R₂ contains a carboxylate, are capable of forming base salts withvarious pharmacologically acceptable cations. Examples of such saltsinclude the alkali metal or alkaline-earth metal salts and particularly,the sodium and potassium salts. These salts are all prepared byconventional techniques. The chemical bases which are used as reagentsto prepare the pharmaceutically acceptable base salts of this inventionare those which form non-toxic base salts with the herein describedacidic compounds of formula I. These non-toxic base salts include thosederived from such pharmacologically acceptable cations as sodium,potassium calcium and magnesium, etc. These salts can easily be preparedby treating the corresponding acidic compounds with an aqueous solutioncontaining the desired pharmacologically acceptable cations, and thenevaporating the resulting solution to dryness, preferably under reducedpressure. Alternatively, they may also be prepared by mixing loweralkanolic solutions of the acidic compounds and the desired alkali metalalkoxide together, and then evaporating the resulting solution todryness in the same manner as before. In either case, stoichiometricquantities of reagents are preferably employed in order to ensurecompleteness of reaction of maximum product of yields of the desiredfinal product.

The preferred salt of(R)-5-(2-phenylsulphonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indolein solid dosage forms is the crystalline, polymorphic α-form of thehydrobromide salt of the compound. The α-form is crystalline, ofsuitable melting point, non-hygroscopic, compressible and possessessolid-state stability, coupled with acceptable solubility anddissolution behavior. The α-form can be produced using methods know inthe art, including, for example, by any of the following three routes.The first route involves treatment of(R)-5-(2-phenylsulphonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indolein a suitable solvent, preferably acetone, at room temperature, with anaqueous solution of hydrogen bromide (e.g., 49%), followed bycrystallization of the isolated crude oil from a suitable solvent,preferably 2-propanol, thus affording the o-form. The second routeinvolves first forming the β-form by treatment of(R)-5-(2-phenylsulphonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indolein a suitable solvent, preferably acetone or a ether solvent such astetrahydrofuran or 1,2-dimethoxyethane, more preferably1,2-dimethoxyethane, at a temperature of from 0 to 10° C., with anaqueous solution of hydrogen bromide (e.g., 49%), furnishing the β-form.Crystallization of the β-form from a suitable solvent, preferablyaqueous acetone, followed by slurrying of the resulting mixture, givesthe desired s-form. The third route involves treatment of(R)-5-(2-phenylsulphonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indolein a suitable solvent, preferably acetone, at from 0° to 5° C. with anaqueous solution of hydrogen bromide (e.g., 62%) and then slurrying ofthe reaction mixture, optionally followed by heating under reflux,cooling and further slurrying, provides the required s-form.

The preferred salt of(R)-5-(methylaminosulfonylmethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indoleis the fumarate salt thereof, which can be prepared by combining(R)-5-(methylaminosulfonyl-methyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indolewith about one equivalent of fumaric acid in methanol. The methanol isthen distilled out and replaced with an equal amount of acetonitrile,thus causing crystallization of the salt.

The compounds of the formula I and the pharmaceutically acceptable saltsthereof (hereinafter, also referred to as the active compounds of theinvention) are useful psychotherapeutics and are potent serotonin(5-HT₁) agonists and may be used in the treatment of depression,anxiety, eating disorders, obesity, drug abuse, cluster headache,migraine, chronic paroxysmal hemicrania and headache associated withvascular disorders, pain, and other disorders arising from deficientserotonergic neurotransmission. The compounds can also be used ascentrally acting antihypertensives and vasodilators.

The active compounds of the invention are evaluated as anti-migraineagents by testing the extent to which they mimic sumatriptan incontracting the dog isolated saphenous vein strip (P. P. A. Humphrey etal., Br. J. Pharmacol., 94, 1128 (1988)). This effect can be blocked bymethiothepin, a known serotonin antagonist. Sumatriptan is known to beuseful in the treatment of migraine and produces a selective increase incarotid vascular resistance in the anaesthetized dog. It has beensuggested (W. Fenwick et al., Br. J. Pharmacol., 96, 83 (1989)) thatthis is the basis of its efficacy.

EC₅₀ 's for the compounds of formula I tested for contracting the dogisolated saphenous vein strip, using the procedure referred to above,were less than 10⁻⁴ M.

The active compounds of the present invention are also evaluated via theinhibition of plasma protein extravasation response within the duramater of guinea pigs following unilateral electrical trigeminal ganglionstimulation. The extent to which they mimic sumatriptan, in terms ofboth potency and efficacy, is determined in this assay. The procedure isperformed on male Hartley guinea pigs (200-250 g, Charles RiverLaboratories, Wilmington, Mass., U.S.A.) as described in Markowitz etal., J. Neurosci., 7 (12), 4129-4136 (1987) and also in Lee, et al.,Brain Reseach, 626, 303-305 (1993). The procedure briefly consists ofplacing pentobarbitone-anesthetized animals in a stereotaxic frame. ¹²⁵I-BSA (bovine serum albumin) (50μCi/kg⁻¹) is first injected into thefemoral vein, followed 5 minutes later by drug or vehicle. Bipolarelectrodes are then lowered into the trigeminal ganglia, and the rightganglion is stimulated for 5 minutes (1.2 mA, 5 Hz, 5 msec). The animalis then perfused with saline through the left cardiac ventricle andsacrificed, and the dura mater is dissected, weighed, and counted forradioactivity. Cpm/mg wet weight values are determined for the right vsleft dura mater, and a ratio for the stimulated vs unstimulated sides isgenerated for each animal. Unpaired student's t-test is used tostatistically compare these ratio values in respective groups treatedwith vehicle or drug. The M.E.D. (minimally effective dose) for a givencompound is the lowest dose for which the mean value of this ratio issignificantly lower than that obtained for the vehicle-treated group.The effect of the drugs in these assays can be partially blocked bymetergoline, a known serotonin antagonist.

A similar procedure to the one described above can be performed on rats,as described in Matsubara, et al., Br. J. Pharmacol., 104, 3 (1991).

The active compounds of the invention may also be useful in thetreatment of headache associated with meningeal irritation, includingbacterial, fungal, viral, parasitic, and chemical meningitis, acquiredimmune deficiency syndrome (AIDS) meningovascular inflammation, andsubarachnoid hemorrhage. [See W. S. Lee, et al., Evidence UsingConformationally Restricted Sumatriptan Analogues, CP-122,288 andCP-122,638, that 5-HT_(1D) Receptors Do Not Mediate Blockade ofNeurogenic Inflammation, 23rd Annual Meeting of the Society forNeuroscience, Washington, D.C., Nov. 7-12, 1993, Abstract #565.6; K.Nozaki, et al., CP-93,129, Sumatriptan, Di-hydroergotamine Block c-fosExpression Within Rat Trigeminal Nucleus Caudalis Caused by ChemicalStimulation of The Meninges, Br. J. Pharmacol. (1992), 1.06, 409; andLee, et al, Brain Research, 626, 303-305 (1993).]

The compositions of the present invention may be formulated in aconventional manner using one or more pharmaceutically acceptablecarriers. Thus, the active compounds of the invention may be formulatedfor oral, buccal, intranasal, parenteral (e.g., intravenous,intramuscular or subcutaneous) or rectal administration or in a formsuitable for administration by inhalation or insufflation.

The compounds of the present invention may be useful in the treatment ofa considerable number of diseases. These include dermatologicaldisorders, including psoriasis; eczema and atopic eczematous dermatitis;intractable itch (pruritus), including itch associated with livercirrhosis, cancer and haemodialysis; burns and scalds; sunburn; insectbites, urticaria and sweat gland abnormalities. Other dermatologicaldisorders include bullous penphgoid, photo dermatoses, skin blisters,adult acne, chicken pox and dermatitis herpetifunus.

Other diseases which may be treated with the compounds of the presentinvention are peripheral neurophathies including postherpetic neuralgia,diabetic neuropathies such as peripheral polyneuropathy andradiculopathy; causalgia and reflex sympathetic dystrophy;post-mastectomy neuralgia; post-surgical neuralgia and pain; vulvarvestibulitis; phantom limb pain; thalamic syndrome (central post-strokepain); temporo mandibular joint syndrome; metarsalgia (Morton'sneuralgia); and neurogenic pain from nerve compression caused, forexample, by a prolapsed intervertebral disc or carpal and tarsal tunnelsyndromes.

The above-mentioned compounds may also be useful in alleviatingarthritis, including osteoarthritis, rheumatoid arthritis, systemiclupus erythrematosus, fibromyalgia, ankylosing spondilitis andtendinitis. They are also effective against gastrointestinal andurogenital diseases including cystitis, gastroesophargeal reflux,gastritis, urge continence, inflammatory bowel disease and irritablebowel syndrome; they are effective in regulatory gastrointestinal tractmotility.

The compounds may also be used in the treatment of headache asociatedwith substances or their withdrawal (e.g. drug withdrawal), tensionheadache, pediatric migraine and prophylaxis of migraine andpost-traumatic dysautonomic cephalgia.

They may also be used for treating orofacial pain (for example toothacheand pain of dental origin, earache, TMJ pain, sinus pain, myofacialpain, non-arthritic and non-musculoskeletal cervical pain), mouthulcers, Meniere's disease and atypical facial neuralgia, and alsoallergic and chronic obstructive airways diseases such as rhinitis,conjunctivitis, bronchial oedema, bronchial asthma, neurologicalpulmonary oedema (adult respiratory disease syndrome), anaphylaxis andangioedema. The compounds are also efficacious in treating ocularpressure or glaucoma and ocular inflammation.

It is believed that the compounds of formula I and their salts areefficacious against emesis caused by several factors not associated withmigraine, including emesis induced by anaesthesia, cancer chemotherapyand by motion (seasickness, space and airsickness).

The activity of the compounds as anti-emetics may be demonstrated by themethod of Tatersall et al and Bountra et al (European Journal ofPharmacology, 250 (1993) R5 and 249 (1993) R₃ -R₄). In this method theextent to which they reduce the latency or the number of retches and/orvomits induced by emetogins in the conscious ferret compared tovehicle--treated animals is measured. It is found that the compounds areeffective against emesis caused by a wide range of emetogeny, extendingfrom local irritants to anti-cancer radiation treatment.

Compounds of formula I described above but for the fact that one or morehydrogen, oxygen, or nitrogen atoms are replaced by radioactive isotopesthereof. Such radiolabelled compounds are useful as research ordiagnostic tools in metabolism pharmacokinetic studies and in bindingassays. Specific applications could include the discovery of novelreceptors involved in the pathogenesis of neurogenic inflammation,leading to diseases such as migraine. Isotopes included among theradiolabelled forms of these compounds are the ³ H and ¹⁴ C isotopesthereof (e.g. the 7-² H, 7-³ H, and N-(³ H₃)-methyl[i.e., having CT₃ onthe pyrrolidinyl nitrogen]), for example,(R)-N-methyl-3-(1-methyl-2-pyrrolidinylmethyl)-1H-[7-²H]-indol-5-yl]methanesulfonamide,(R)-N-methyl-[3-(1-methyl-2-pyrrolidinylmethyl)-1H-[7-³H]-indol-5-yl]methanesulfonamide, and (R)-N-methyl-[3-(1-(³H₃)methyl-2-pyrrolidinylmethyl)-1H-indol-5-yl]methanesulphonamide. The7-² H and 7-³ H derivatives of the invention can be prepared by thedeuteration or tritiation of the corresponding 7-bromo-derivative,preferably in the presence of pre-reduced Pearlman's catalyst in anorganic solvent such as ethanol. The ³ H₃ (i.e., tri-tritiatedderivative) can be prepared by the reaction of the correspondingcompound having no substitution on the pyrrolidinyl nitrogen, preferablyas a salt such as the hydrobromide, with 3H methyl iodide, preferably inthe presence of a base such as potassium carbonate.

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents (e.g.pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose orcalcium phosphate); lubricants (e.g. magnesium stearate, talc orsilica); disintegrants (e.g. potato starch or sodium starch glycollate);or wetting agents (e.g. sodium lauryl sulphate). The tablets may becoated by methods well known in the art. Liquid preparations for oraladministration may take the form of, for example, solutions, syrups orsuspensions, or they may be presented as a dry product for constitutionwith water or other suitable vehicle before use. Such liquidpreparations may be prepared by conventional means with pharmaceuticallyacceptable additives such as suspending agents (e.g. sorbitol syrup,methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g.lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily estersor ethyl alcohol); and preservatives (e.g. methyl or propylp-hydroxybenzoates or sorbic acid).

For buccal administration the composition may take the form of tabletsor lozenges formulated in conventional manner.

The active compounds of the invention may be formulated for parenteraladministration by injection, including using conventionalcatheterization techniques or infusion. Formulations for injection maybe presented in unit dosage form e.g. in ampules or in multi-dosecontainers, with an added preservative. The compositions may take suchforms as suspensions, solutions or emulsions in oily or aqueousvehicles, and may contain formulating agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form for reconstitution with a suitablevehicle, e.g. sterile pyrogen-free water, before use.

The active compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g., containingconventional suppository bases such as cocoa butter or other glycerides.

For intranasal administration or administration by inhalation, theactive compounds of the invention are conveniently delivered in the formof a solution or suspension from a pump spray container that is squeezedor pumped by the patient or as an aerosol spray presentation from apressurized container or a nebulizer, with the use of a suitablepropellant, e.g. dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. The pressurized containeror nebulizer may contain a solution or suspension of the activecompound. Capsules and cartridges (made, for example, from gelatin) foruse in an inhaler or insufflator may be formulated containing a powdermix of a compound of the invention and a suitable powder base such aslactose or starch.

A proposed dose of the compound(R)-5-(methylaminosulfonylmethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indolefor oral, parenteral or buccal administration to the average adult humanfor the treatment of the conditions referred to above (e.g., migraine)is 0.1 μg to 200 mg of the active ingredient per unit dose which couldbe administered, for example, 1 to 4 times per day. In one embodiment,the pharmaceutical composition includes 0.1 μg to less than 0.1 mg ofthe active ingredient per unit dose, and in another embodiment, thepharmaceutical composition includes 0.1 μg to 0.09 mg of the activeingredient per unit dose.

A proposed dose of the compound(R)-5-(aminosulfonylmethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indolefor oral, parenteral or buccal administration to the average adult humanfor the treatment of the conditions referred to above (e.g., migraine)is 0.1 μg to 200 mg of the active ingredient per unit dose which couldbe administered, for example, 1 to 4 times per day. In one embodiment,the pharmaceutical composition includes 0.1 μg to less than 0.1 mg ofthe active ingredient per unit dose, and in another embodiment, thepharmaceutical composition includes 0.1 μg to 0.09 mg of the activeingredient per unit dose.

A proposed dose of the compound(R)-5-(methylaminosulfonylmethyl)-3-(pyrrolidin-2-ylmethyl)-1H-indolefor oral, parenteral or buccal administration to the average adult humanfor the treatment of the conditions referred to above (e.g., migraine)is 0.01 μg to 200 mg of the active ingredient per unit dose which couldbe administered, for example, 1 to 4 times per day. In one embodiment,the pharmaceutical composition includes 0.01 μg to less than 0.1 mg ofthe active ingredient per unit dose, and in another embodiment, thepharmaceutical composition includes 0.01 μg to 0.09 mg of the activeingredient per unit dose.

A proposed dose for the other active compounds of the invention fororal, parenteral or buccal administration to the average adult human forthe treatment of the conditions referred to above (e.g., migraine) is0.1 to 200 mg of the active ingredient per unit dose which could beadministered, for example, 1 to 4 times per day.

Aerosol formulations for treatment of the conditions referred to above(e.g., migraine) in the average adult human are preferably arranged sothat each metered dose or "puff" of aerosol contains 0.01 μg to 1000 μgof the compounds(R)-5-(methylaminosulfonylmethyl)-3-(N-methyl-pyrrolidin-2-ylmethyl)-1H-indole,(R)-5-(aminosulfonylmethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indoleor(R)-5-(methylaminosulfonylmethyl)-3-(pyrrolidin-2-ylmethyl)-1H-indole.In one embodiment, each metered dose or "puff" of aerosol contains 0.01μg to less than 20 μg of the active ingredient, and in anotherembodiment, each metered dose or "puff" of aerosol contains 0.01 μg to19 μg of the active ingredient. The overall daily dose with an aerosolwill be within the range 0.05 μg to 10 mg. In one embodiment, theoverall daily dose with an aerosol will be within the range 0.05 μg toless than 100 μg of the active ingredient, and in another embodiment,the overall daily dose with an aerosol will be within the range 0.05 μgto 99 μg of the active ingredient. Administration may be several timesdaily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or 3doses each time.

Aerosol formulations for treatment of the conditions referred to above(e.g., migraine) in the average adult human are preferably arranged sothat each metered dose or "puff" of aerosol contains 20 μg to 1000 μg ofthe other compounds of the invention. The overall daily dose with anaerosol will be within the range 100 μg to 10 mg. Administration may beseveral times daily, for example 2, 3, 4 or 8 times, giving for example,1, 2 or 3 doses each time.

The above-cited ranges will generally be those most desirably employedin the administration of the active compounds. Nevertheless, variationsmay still occur depending on the age, weight, the patient's individualresponse to the compound being administered, as well as the severity ofthe condition for which he, or she, is being treated and the type ofpharmaceutical formulation chosen and time period and interval at whichsuch administration is carried out. In some instances, dosage levelsbelow the lower limit of the aforesaid ranges may be more than adequate,while in other cases still larger doses may be employed without causingharmful side effects provided that such higher dose levels are firstdivided into small doses for administration throughout the day.

The following Examples illustrate the preparation of the compounds ofthe present invention. Melting points are uncorrected. NMR data arereported in parts per million (δ) and are referenced to the deuteriumlock signal from the sample solvent. Specific rotations were measured atroom temperature using the sodium D line (589 nm).

Commercial reagents were utilized without further purification.Chromatography refers to column chromatography performed using 32-63 μmsilica gel and executed under nitrogen pressure or compressed airpressure (flash chromatography) or gravity conditions. Room temperaturerefers to 20°-25° C.

EXAMPLE 1 General Procedure for the Reduction ofBenzyloxy-carbonyl-Pyrrolidin-2-ylcarbonyl-1H-indole,N-Benzyloxy-carbonyl-azetidin-2-ylcarbonyl-1H-indoles, orN-Benzyloxy-carbonyl-piperidin-2-ylcarbonyl-1H-indoles Forming3-(N-Methyl-Pyrrolidin-2-ylmethyl)-1H-indoles,3-(N-Methylazetidin-2-ylmethyl)-1H-indoles, or3-(N-Methylpiperidin-2-ylmethyl)-1H-indoles, respectively.

To a stirred solution of (R)- or(S)-(N-benzyloxycarbonylpyrrolidin-2-ylcarbonyl)-1H-indole, (R)-, (S),or (R,S)-(N-benzyloxycarbonylazetidin-2-ylcarbonyl)-1H-indole, or (R)-,(S)-, or (R,S)-(N-benzyloxycarbonylpiperidin-2-ylcarbonyl)-1H-indole,(5.00 mmol) in anhydrous tetrahydrofuran (20 mL) at room temperatureunder nitrogen was carefully added lithium aluminum hydride (0.57 g,15.0 mmol, 3.0 eq) as a powder, and the resulting mixture was stirred atroom temperature under nitrogen for 1 hour. The mixture was then heatedat reflux (66° C.) under nitrogen for 12 hours. The reaction was thenquenched with successive additions of water (0.5 mL), aqueous sodiumhydroxide (20%, 0.5 mL), and then additional water (1.0 mL), and theresulting mixture filtered through diatomaceous earth (Celite(trademark)). The solids were then washed with copious amounts of ethylacetate (50 mL). The combined filtrate was then washed with water (20mL), dried (MgSO₄), and evaporated under reduced pressure. The residuewas then column chromatographed using silica gel (50 g) and elution withthe appropriate solvent system to afford the3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole,3-(N-methylazetidin-2-ylmethyl)-1H-indole, or3-(N-methylpiperidin-2-ylmethyl)-1H-indole. Following this procedure thefollowing compounds were prepared:

A. (S)-5-Methoxy-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole

(S)-(N-Benzyloxycarbonylpyrrolidin-2-ylcarbonyl)-5-methoxy-1H-indole wasused. The chromatographic eluent was 8% triethylamine in ethyl acetateto afford the title compound (yields ranged from 22 to 57%) as an oil:IR (CHCl₃) 3475, 1625, 1585, 1480, 1455 cm⁻¹ ; ¹ H NMR (CDCl₃) δ8.13 (brs, 1H), 7.23 (d, J=8.8 Hz, 1H), 7.04 (d, J=2.4 Hz, 1H), 6.97 (d, J=2.2Hz, 1H), 6.84 (dd, J=2.4 and 8.8 Hz, 1H), 3.86 (s, 3H), 3.17-3.10 (m,2H), 2.58 (dd, J=9.9 and 13.9 Hz, 1H), 2.50-2.40 (m, 1H), 2.47 (s, 3H),2.26-2.17 (m, 1H), 1.89-1.72 (m, 2H), 1.70-1.52 (m, 2H); ¹³ C NMR(CDCl₃) δ153.8, 131.4, 128.2, 122.7, 113.9, 111.8, 111.7, 101.1, 66.6,57.5, 56.0, 40.8, 31.5, 30.0, 21.9; LRMS, m/z (relative intensity) 244(M⁺, 7), 160 (20), 145 (16), 117 (21), 84 (100); HRMS: calculated forC₁₅ H₂₀ N₂ O: 244.1573; found: 244.1575; [α]²⁵ _(D) =-96° (CHCl₃,c=1.0).

B. (R)-5-Methoxy-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole

(R)-(N-Benzyloxycarbonylpyrrolidin-2-ylcarbonyl)-5-methoxy-1H-indole wasused. The chromatographic eluent was 8% triethylamine in ethyl acetateto afford the title compound (yields ranged from 13 to 61%) as an oilwhose spectral and physical properties were identical with the spectraland physical properties of the title compound of Example 1A with theexception of specific rotation of plane polarized light: [α]²⁵ _(D)=+100° (CHCl₃, c=1.0). HRMS: calculated for C₁₅ H₂₀ N₂ O; 244.1573;found: 244.1547.

C. (R)-5-Dibenzylamino-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole

(R)-3-(N-Benzyloxycarbonylpyrrolidin-2-ylcarbonyl)-5-dibenzylamino-1H-indolewas used. Column chromatography using elution with methylenechloride/methanol/ammonium hydroxide [9:1:0.1] afforded the titlecompound as a pale green foam: ¹ H NMR (CDCl₃) δ7.82 (br s, NH),7.35-7.19 (m, 10H), 7.20 (d, J=8.6 Hz, 1H), 6.95 (d, J=2.1 Hz, 1H), 6.85(dd, J=2.3 and 8.7 Hz, 1H), 6.80 (d, J=2.2 Hz, 1H), 4.65 (s, 4H),3.25-3.02 (m, 2H), 2.52 (dd, J=9.5 and 13.9 Hz, 1H), 2.39-2.15 (m, 2H),2.30 (s, 3H), 1.85-1.40 (m, 4H); ¹³ C NMR (CDCl₃) 6 143.2, 139.7, 130.5,128.5, 128.2, 127.3, 126.8, 122.9, 112.5, 112.2, 111.8, 103.4, 67.0,57.4, 56.4, 40.6, 31.4, 29.7, 21.9. HRMS: calculated for C₂₈ H₃₁ N₃409.2520. Found 409.2475.

D. (R)-5-Methoxy-3-(N-methylpiperid-2-ylmethyl)-1H-indole

(R)-3-(N-Benzyloxycarbonylpiperid-2-ylcarbonyl)-5-methoxy-1H-indole wasused. Column chromatography using elution with 6% triethylamine in ethylacetate afforded the title compound as a white foam: ¹³ C NMR (CDCl₃)δ153.7, 131.4, 128.3, 123.3, 113.2, 111.7, 111.6, 101.2, 64.4, 57.2,55.9, 43.4, 31.0, 28.8, 25.9, 24.1; [α]²⁵ _(D) =+67° (CDCl₃, c=1.0);HRMS: calculated for C₁₆ H₂₂ N₂ O: 258. 1734. Found: 258. 1710.

E. (S)-5-Methoxy-3-(N-methylazetidin-2-ylmethyl)-1H-indole

(S)-3-(N-Benzyloxycarbonylazetidinyl-2-ylcarbonyl)-5-methoxy-1H-indolewas used. The chromatographic eluent was 8% triethylamine in ethylacetate to afford the title compound as a white solid: mp, 118.0°-120.0°C.; ¹³ C NMR (CDCl₃) δ153.8, 131.6, 128.0, 122.9, 112.3, 111.9, 111.8,101.0, 68.5, 56.0 53.1, 44.7, 32.4, 25.0; [α]²⁵ _(D) =-44° (CHCl₃,c=1.0). Anal. calcd for C₁₄ H₁₈ N₂ O: C, 73.01; H, 7.88, N, 12.16.Found: C, 72.65; H, 7.91; N, 12.06.

F. (R,S)-5-Methoxy-3-(N-methylazetidin-2-ylmethyl)-1H-indole

(R,S)-3-(N-Benzyloxycarbonylazetidinyl-2-ylcarbonyl)-5-methoxy-1H-indolewas used. The chromatographic eluet was 10% triethylamine in ethylacetate to afford the title compound as a white solid: mp, 116.0°-119.0°C.; Anal. calcd for C₁₄ H₁₈ N₂ O: C, 73.01; H, 7.88; N, 12.16. Found: C,72.61; H, 7.99; N, 12.10.

EXAMPLE 2 General Method for the Hydrogenation of5-(2-Sulfonyl-ethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indoles toForm 5-(2-Sulfonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indoles

A solution of5-(2-sulfonylethenyl)-3-(N-methylpyrrolidin-2-yl)-1H-indole (0.47 mmol)and 10% Pd/C (0.150 g) in ethanolic hydrogen chloride [prepared fromabsolute ethanol (10 mL) and acetyl chloride (43 μL)] andN,N-dimethylformamide (7.5 mL) was shaken under a hydrogen atmosphere(15 psi) at room temperature for 20 hours. The resultant reactionmixture was filtered through diatomaceous earth (Celite (trademark)),washed with absolute ethanol, and the combined filtrates were evaporatedunder reduced pressure. The residue was partitioned between ethylacetate and water. The organic phase was separated, washed with water(3×), brine (1×), dried (Na₂ SO₄), and evaporated under reduced pressureto afford a yellow oil. Column chromatography of this oil using silicagel and elution with methylene chloride/absolute ethanol/ammonia(90:10:1) afforded the appropriate5-(2-Ethylsulfonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole.Following this procedure, the following compounds were prepared:

A.(R)-5-(2-Ethylsulfonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole

(R)-5-trans-(2-Ethylsulfonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole(Example 4A) was reduced as described above. Chromatography afforded thetitle compound (0.33 mmol, 70%) as a gum: TLC (CH₂ Cl₂ : EtOH:NH₃,90:10:1): R_(f) =0.3; [α]²⁵ _(D) =+62° (methanol, c=0.10). Anal. Calcdfor CC₁₈ H₂₆ N₂ O₂ S•0.05 CH₂ Cl₂ : C, 63.21; H, 7.67; N, 8.17; found:C, 63.55; H, 7.61; N, 8.41.

B.(R)-5-(2-Methylaminosulfonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole

(R)-5-trans-(2-Methylaminosulfonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole(Example 4B) was reduced as described above. Chromatography afforded thetitle compound (65%) as a foam. Anal. Calcd for C₁₇ H₂₅ N₃ O₂ S•0.1 CH₂Cl₂ : C, 59.71; H, 7.39; N, 12.12; found: C, 59.66; H, 7.14; N, 11.90.

EXAMPLE 3 General Synthesis of3-(N-Benzyloxycarbonylpyrrolidin-2-ylcarbonyl)-1H-indoles3-(N-Benzyloxycarbonylazetidin-2-ylcarbonyl)-1H-indoles, or3-(N-Benzyloxycarbonylpiperidin-2-ylcarbonyl)-1H-indoles

Two solutions containing the reactants were prepared separately asfollows. To a stirred solution of N-carbobenzyloxyproline (D or L, 3.10g, 12.4 mmol, 1 eq) or N-carbobenzyloxyazetidine-2-carboxylic acid (R orS or racemate, 12.4 mmol) or N-carbobenzyloxypipecolinic acid (R or S orracemate, 12.4 mmol) in anhydrous methylene chloride (7 mL) with onedrop dimethylformamide was added oxalyl chloride (1.60 mL, 18.4 mmol,1.5 eq), and the resulting effervescing solution was stirred at roomtemperature under nitrogen for 1.5 hours. The solution was thenevaporated under reduced pressure, and any remaining solvent was removedfrom the residual oil using high vacuum to afford theN-benzyloxycarbonylproline acid chloride. At the same time, a solutionof ethylmagnesium bromide (3.0M in ether, 4.13 mL, 12.4 mmol, 1 eq) wasadded to a stirred solution of the indole (12.4 mmol) in anhydrous ether(50 mL), and this cloudy solution was heated at reflux under nitrogenfor 1.5 hours to form the indolemagnesium bromide salt. The proline acidchloride was then dissolved in methylene chloride or ethyl ether (3 mL),and this solution was added dropwise to the stirred solution of theindolemagnesium bromide salt at room temperature, and the resultantreaction mixture was stirred at room temperature under nitrogen for 1hour. A saturated solution of sodium hydrogen carbonate (25 mL) andethyl acetate (50 mL) was then added to the reaction mixture, and thismixture was vigorously stirred for 15 minutes. The resulting mixture wasfiltered through diatomaceous earth (Celite (trademark)), the solidswashed with copious amounts of ethyl acetate, and the ethyl acetatelayer was separated from the aqueous layer which was extracted withethyl acetate (2×25 mL). All ethyl acetate extracts were combined,dried, and evaporated under reduced pressure. The residual oil/solid wasflash chromatographed using silica gel (250 g) and eluted with anappropriate solvent system to afford the desired3-(N-benzyloxycarbonylpyrrolidin-2-ylcarbonyl)indole,3-(N-benzyloxycarbonylazetidin-2-ylcarbonyl)-1H-indole,or 3-(N-benzyloxycarbonylpiperidin-2-ylcarbonyl)-1H-indole.

A.(S)-3-(N-Benzyloxycarbonylpyrrolidin-2-ylcarbonyl)-5-methoxy-1H-indole

N-Carbobenzyloxy-L-proline was used. Chromatography using 40-60% ethylacetate gradient in hexanes afforded the title compound (yields rangedfrom 27 to 43%) as a white powder. Recrystallization in ethylacetate/hexanes afforded an analytical sample as a white crystallinesolid: mp, 164.0°-165.0° C.; IR (KBr) 3250, 1695, 1660, 1585, 1520,1485, 1450, 1425 cm⁻¹ ; ¹ H NMR (CDCl₃) [Note: the spectrum of the titlecompound appears as a 1:3 mixture of diastereomers due to slow inversionof the amide nitrogen on an NMR time scale. Therefore, the ¹ H NMR willbe interpreted for each compound separately with the more abundantconformer quoted first]δ [more abundant conformer] 9.83 (br s, 1H), 7.53(d, J=3.4 Hz, 1H), 7.42-7.30 (m, 6H), 7.00 (d, J=8.9 Hz, 1H), 6.69 (dd,J=2.4 and 9.0 Hz, 1H), 5.25 (d, J=12.9 Hz, 1H), 5.14 (d, J=12.5 Hz, 1H),5.07-4.99 (m, 1H), 3.74 (s, 3H), 3.78-3.55 (m, 2H), 2.28-1.84 (m, 4H)and δ [less abundant conformer] 9.28 (br s, 1H), 7.90 (d, J=2.3 Hz, 1H),7.59 (d, J=3.4 Hz, 1H), 7.24 (d, J=9.0 Hz, 1H), 7.06-6.90 (m, 5H), 6.88(dd, J=2.7 and 9.0 Hz, 1H), 5.07-4.99 (m, 2H), 4.96-4.88 (m, 1H), 3.86(s, 3H), 3.78-3.55 (m, 2H), 2.28-1.84 (m, 4H); LRMS, m/z (relativeintensity) 379 (8), 378 (M⁺,33), 204 (31), 174 (64), 160 (41), 146 (10),91 (100). Analysis: calculated for C₂₂ H₂₂ N₂ O₄ : C, 69.83; H, 5.86; N,7.40; found: C, 69.81; H, 5.67; N, 7.40.

B. (R)-3-(N-Benzyloxycarbonylpyrrolidin-2-ylcarbonyl)-5-methoxy-1H-indole

N-Carbobenzyloxy-D-proline was used. Chromatography using 40-60% ethylacetate gradient in hexanes afforded the title compound (yields rangedfrom 25 to 36%) as a white powder. Recrystallization in ethylacetate/hexanes afforded an analytical sample as a white crystallinesolid: mp, 165°-166° C. The spectral and physical data for the titlecompound were identical in all respects with the spectral and physicaldata of its enantiomer (the title compound of Example 3A); HRMS:calculated for C₂₂ H₂₂ N₂ O₄ : 378.1582; found: 378.1573.

C.(R)-3-(N-Benzyloxycarbonylpyrrolidin-2-ylcarbonyl)-5-dibenzylamino-1H-indole

N-Carbobenzyloxy-D-proline was used. Trituration of the extractionresidue with diethyl ether afforded the title compound as a solid: top,176.0°-177.0° C.; LRMS (m/z, relative intensity) 543 (100, M⁺), 453(10), 407 (7), 339 (40), 307 (10), 247 (10), 154 (38); [α]²⁵ _(D) =+112°(THF, c=1.0); Anal. calcd for C₃₅ H₃₃ N₃ O₃ : C, 77.32; H, 6.12; N,7.73. Found: C, 77.35; H, 6.30; N, 7.66.

D. (R)-3-(N-Benzyloxycarbonylpiperid-2-ylcarbonyl)-5-methoxy-1H-indole

N-Carbobenzyloxy-D-pipecolinic acid was used. Column chromatographyusing elution with 10% ether in methylene chloride afforded the titlecompound as a tan foam: LRMS (m/z, relative intensity) 392 (90, M⁺), 348(27), 284 (13), 273 (12), 258 (15), 237 (47), 217 (58), 173 (100). Anal.calculated for C₃₅ H₃₃ N₃ O₂ : C, 69.22; H, 5.53; N, 7.69. Found: C,69.35; H, 5.33; N, 7.64.

E.(S)-3-(N-Benzyloxycarbonylazetidinyl-2-ylcarbonyl)-5-methoxy-1H-indole

(S)-N-Carbobenzyloxyazetidine-2-carboxylic acid was used. Trituration ofthe extract residue with absolute methanol afforded the title compoundas a white solid: mp, 199.0°-200.0° C. Anal. calcd for C₂₁ H₂₀ N₂ O₄ :C, 69.22; H, 5.53; N, 7.69. Found: C, 69.35; H, 5.33; N, 7.64.

F.(R,S)-3-(N-Benzyloxycarbonylazetidinyl)-2-ylcarbonyl)-5-methoxy-1H-indole

(R,S)-N-Carbobenzyloxyazetidine-2-carboxylic acid was used. Triturationof the extract residue with absolute methanol afforded the titlecompound as a white solid: mp, 199.0°-200.0° C. Anal. calcd for C₂₁ H₂₀N₂ O₄ : C, 69.22; H, 5.53; N, 7.69. Found: C, 68.85; H, 5.47; N, 7.57.

EXAMPLE 4 General Method for the Synthesis of5-trans-(2-Sulfonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indoles

A mixture of the appropriate vinyl sulfone (1.17 mmol, 1.4 eq),tri-o-tolylphosphine (0.075 g, 0.25mmol, 0.33 eq), palladium (II)acetate (0.013 g), triethylamine (0.25 mL, 1.79 mmol, 2 eq), and(R)-5-bromo-3-(N-methylpyrrolidinylmethyl)-1H-indole (0.25 g, 0.85 mmol)in anhydrous acetonitrile (3 mL) was heated at reflux under nitrogen for17 hours. The resultant reaction mixture was evaporated under reducedpressure, and the residue was column chromatographed using silica geland elution with methylene chloride/absolute ethanol/ammonia (90:8:1) toafford the title compound.

A.(R)-5-trans-(2-Ethylsulfonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole

Ethyl vinyl sulfone was used, and chromatography afforded the titlecompound (65%) as a white foam: TLC (CH₂ Cl₂ /EtOH/NH₃, 90:10:1):R_(f)=0.5. Analysis: calculated for C₁₈ H₂₄ N₂ O₂ S•0.2 CH₂ Cl₂ : C, 62.55;H, 7.04; N, 8.02; found: C, 62.65; H, 6.94; N, 7.92.

B.(R)-5-trans-(2-Methylaminosulphonylethenyl)-3-(N-methyl-pyrrolidin-2-ylmethyl)-1H-indole

N-methylvinylsulfonamide was used, and chromatography afforded the titlecompound (71%) as a white foam. Analysis: calculated for C₁₇ H₂₃ N₃ O₂S•0.1 CH₂ Cl₂ : C, 60.06; H, 6.84; N, 12.29; found: C, 59.74; H, 6.77;N, 11.97.

EXAMPLE 5 General Procedure for the Hydride Reduction of3-(N-Benzyloxycarbonyl-pyrrolidin-2-ylmethyl)-1H-indoles and3-(N-Benzyloxycarbonylpiperid-2-ylmethyl)-1H-indoles Forming3-(N-Methylpyrrolidin-2-ylmethyl)-1H-indoles and3-(N-Methyliperid-2-ylmethyl)-1H-indoles

To a stirred mixture of lithium aluminum hydride (0.152 g, 4.00 mmol,2eq) in anhydrous tetrahydrofuran (10 mL) at 0° C. was added rapidly asolution of the 3-(N-benzyloxycarbonylpyrrolidin-2-ylmethyl)-1H-indoleor the 3-(N-benzyloxycarbonylpiperid-2-ylmethyl)-1H-indole (2.00 mmol)in anhydrous tetrahydrofuran (5 mL). The resulting mixture is heated atreflux under a nitrogen atmosphere for 3 hours. The reaction mixture iscooled, and water (0.25 mL), 15% aqueous sodium hydroxide (0.25 mL), andthen more water (0.75 mL) were added sequentially. The resulting mixturewas stirred at 25° C. for 30 minutes, filtered, and the filtrate wasevaporated under reduced pressure. The residue was columnchromatographed using silica gel (approximately 50 g) and elution with asolution methylene chloride:methanol:ammonium hydroxide [9:1:0.1] orother appropriate solvent system to afford the corresponding3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole or3-(N-methylpiperid-2-ylmethyl)-1H-indole.

Following this procedure the following compounds were prepared:

A.(R)-5-(Methylaminosulfonylmethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole

(R)-3-(N-Benzyloxycarbonylpyrrolidin-2-ylmethyl)-5-(methylaminosulfonylmethyl)-1H-indolewas used. The reaction residue after aqueous work-up as described abovewas triturated with absolute methanol to afford the title compound as awhite solid: top, 213.0°-214.0° C.; ¹ H NMR (DMSO-d₆) δ10.9 (br s,indole NH), 7.51 (be d, 1H), 7.31 (d, J=8.3 Hz, 1H), 7.16 (br d, 1H),7.08 (br dd, J=8.3 Hz, 1H), 6.82 (br q, sulfonamide NH), 4.35 (s, 2H),3.07-2.95 (m, 2H), 2.54 (d, J=4.7 Hz, 3H), 2.52-2.38 (m, 2H), 2.35 (s,3H), 2.10 (br, q, J=8.2 Hz, 1H), 1.75-1.40 (m, 4H); [α]²⁵ _(D) =+89°(DMSO-d₆, c=1.0); Anal. calcd for C₁₆ H₂₃ N₃ SO₂ : C, 59.79; H, 7.21; N,13.07. Found: C, 59.66; H, 7.29; N, 12.81. M.E.D. for inhibition ofplasma protein extravasation i.v. in guinea pigs, 1.0 pmol per kg.

B. (R)-5-Aminomethyl-3-(N-methylpyrrolidin-2-ylmethyl)-1H-inole

(R)-3-(N-Benzyloxycarbonylpyrrolidin-2-ylmethyl)-5-cyano-1H-indole wasused. Column chromatography using elution with 9:1:0.1 [methylenechloride:methanol:ammonium hydroxide] afforded the title compound as awhite foam: ¹³ C NMR δ135.6, 132.3, 127.5, 123.0, 122.8, 121.4, 117.1,112.8, 111.5, 66.8, 57.2, 46.4, 40.5, 31.2, 29.2, 21.5; HRMS: calculatedfor C₁₅ H₂₁ N₃ 243.1737, found 243.1732.

C.(R,S)-5-(Methylaminosulfonylmethyl)-3-(N-methylpiperid-2-ylmethyl)-1H-indole

(R,S)-3-(N-Benzyloxycarbonylpiperidin-2-ylmethyl)-5-(methylaminosulfonylmethyl)-1H-indolewas used. Column chromatography using elution with 10% triethylamine inethyl acetate afforded the title compound as a clear, colorless oil: ¹³C NMR (DMSO-d₆) δ135.9, 127.7, 124.0, 123.6, 121.0, 119.7, 111.9, 111.1,63.9, 56.7, 56.3, 43.2, 30.5, 29.0 27.9, 25.5, 23.7; LRMS (m/z, relativeintensity) 336 (1, M⁺), 241 (5), 143 (31), 142 (13), 99 (34), 98 (100),70 (16); HRMS calculated for C₁₇ H₂₅ N₃ O₂ S: 336.1745; found: 336.1756.

EXAMPLE 6 General Procedure for the Catalytic Reduction of3-(N-Benzyloxycarbonylpyrrolidin-2-ylmethyl)-1H-indoles and 3-(N-Benzyloxycarbonylpiperid-2-ylmethyl)-1H-indoles Forming3-(Pyrrolidin-2-ylmethyl)-1H-indoles and3-(Piperid-2-ylmethyl)-1H-indoles

A mixture of the 3-(N-benzyloxycarbonylpyrrolidin-2-ylmethyl)-1H-indoleor the 3-(N-benzyloxycarbonylpiperid-2-ylmethyl)-1H-indole (2.00 mmol),10% palladium on carbon (0.20 g), and ammonium formate (1.26 g, 20 mmol,10 eq) in absolute ethanol (15 mL) was stirred under a nitrogenatmosphere for 4 hours. The resulting reaction mixture was filteredthrough diatomaceous earth, and the filtrate was evaporated underreduced pressure. The residue was column chromatographed using silicagel (approximately 50 g) and elution with a solution of methylenechloride: methanol: ammonium hydroxide [8:2:0.2] or other appropriatesolvent system to afford the corresponding3-(pyrrolidin-2-ylmethyl)-1H-indole or 3-(piperid-2-ylmethyl)-1H-indole.

Following this procedure the following compounds were prepared:

A. (R)-5-(Methylaminosulfonylmethyl)-3-(pyrrolidin-2-ylmethyl)-1H-indole

(R)-3-(N-Benzyloxycarbonylpyrrolidin-2-ylmethyl)-5-(methylaminosulfonylmethyl)-1H-indolewas used. Column chromatography as described above afforded the titlecompound as an off-white gum: ¹³ C NMR (DMSO-d₆) δ135.9, 127.5, 123.8,123.7, 120.9, 119.7, 112.4, 111.1, 59.2, 56.6, 45.7, 31.1, 31.0, 29.0,24.6; [α]²⁵ _(D) =+4° (DMSO-d₆, c=1.0); [α]²⁵ _(D) =-14° (EtOH/CHCl₃[1:1], c=1.0); HRMS: calculated for [C₁₅ H₂₁ N₃ O₂ S•H⁺ ]: 308.1433;found: 308.1467. M.E.D. for inhibition of plasma protein extravasationi.v. in guinea pigs, 0.1 pmol per kg.

B. (R)-5-Cyano-3-(pyrrolidin-2-ylmethyl)-1H-indole

(R)-3-(N-Benzyloxycarbonylpyrrolidin-2-ylmethyl)-5-cyano-1H-indole wasused. Column chromatography as described above afforded the titlecompound as an off-white gum: ¹³ C NMR (CDCl₃ /CD₃ OD) δ138.1, 127.2,125.0, 124.4, 124.2, 121.0, 113.4, 112.2, 101.5, 59.5, 50.1, 45.7, 31.3,30.3, 24.7; LRMS (M/Z, relative intensity) 225 (M+,3), 179 (3), 155(10), 70 (100); HRMS: calculated for C₁₄ H₁₅ N₃ 225.1268, found225.1245.

C. (R)-3-(Pyrrolidin-2-ylmethyl)-1H-indole

(R)-3-(N-Benzyloxycarbonylpyrrolidin-2-ylmethyl)-1H-indole was used.Evaporation of the filtrate residue directly afforded the title compoundas a white foam: ¹ H NMR (CDCl₃) δ9.05 (br s, indole NH), 7.50 (d, J=8.6Hz, 1H), 7.23 (d, J=8.6 Hz, 1H), 7.12-6.98 (m, 2H), 6.90 (s, 1H), 4.0(br s, amine NH), 3.36-3.24 (m, 1H), 2.95-2.75 (m, 3H), 2.70-2.58 (m,1H), 1.85-1.50 (m, 3H), 1.45-1.29 (m, 1H); [α]²⁵ _(D) =+18° (CHCl₃,c=1.0).

D. (R)-5-Methoxy-3-(Pyrrolidin-2-ylmethyl)-1H-indole

(R)-3-(N-Benzyloxycarbonylpyrrolidin-2-ylmethyl)-5-methoxy-1H-indole wasused. Evaporation of the filtrate residue directly afforded the titlecompound as a gum: LRMS (m/z, relative intensity) 231 (100, M+), 161(10), 155 (17), 135 (11), 119 (32); [α]²⁵ _(D) =-12° (CHCl₃, c=1.0);Anal, calcd for C₁₄ H₁₈ N₂ O•0.75 C₂ ₄ O₂ [acetic acid salt]: C, 67.61;H, 7.69; N, 10.17. Found: C, 67.74; H, 7.53; N, 9.90.

E. (R,S)-5-(Methylaminosulfonylmethyl)-3-(piperid-2-ylmethyl)-1H-indole

(R,S)-3-(N-Benzyloxycarbonylpiperid-2-ylmethyl)-5-(methylaminosulfonylmethyl)-1H-indolewas used. Column chromatography as described above afforded the titlecompound as a clear, colorless oil: ¹³ C NMR (DMSO-d₆) δ136.0, 127.5,124.2, 123.8, 121.0, 119.8, 111.2, 110.9, 56.8, 56.7, 45.8, 31.7, 31.4,29.0, 25.0, 23.9; LRMS (m/z, relative intensity) 321 (19, M+), 238 (43),227 (21), 144 (99), 143 (100); HRMS: calculated for C₁₆ H₂₃ N₃ O₂ S:321.1513; found: 321.1501.

EXAMPLE 7 General Procedure for the Formulation of3-(N-Benzyloxycarbonylpyrrolidin-2-ylmethyl)-1H-indoles and3-(N-Benzyloxycarbonylpiperid-2-ylmethyl)-1H-indoles Via the PalladiumCatalyzed Cyclization of1-(N-Benzyloxycarbonylpyrrolidin-2-yl)-3-(N-(2-halophenyl)-N-trifluoroacetylamino)propenesand1-(N-Benzyloxycarbonylpiperid-2-yl)-3-(N-(2-halophenyl)-N-trifluoroacetylamino)propenes

A mixture of the1-(N-benzyloxycarbonylpyrrolidin-2-yl)-3-(N-(2-halophenyl)-N-trifluoroacetylamino)propeneor the1-(N-benzyloxycarbonylpiperid-2-yl)-3-(N-(2-halophenyl)-N-trifluoroacetylamino)propene(2.00 mmol), tetrabutylammonium chloride (2.00 mmol), and palladium(II)acetate (0.089 g, 0.40 mmol, 0.2 eq) in a solution of triethylamine (8mL) and anhydrous N,N-dimethylformamide (4 mL) was heated at refluxunder nitrogen for 2 hours. The resulting reaction mixture wasevaporated under reduced pressure, and the residue was partitionedbetween ethyl acetate (25 mL) and water (25 mL). The ethyl acetate layerwas removed, and the aqueous layer was extracted with additional ethylacetate (25 mL). The organic extracts were combined, dried (MgSO₄), andevaporated under reduced pressure. The residue was columnchromatographed using silica gel (approximately 50 g) and elution witheither a diethyl ether gradient in methylene chloride or an acetonegradient in methylene chloride to afford the corresponding3-(N-benzyloxycarbonylpyrrolidin-2-ylmethyl)-1H-indole or the3-(N-benzyloxycarbonylpiperid-2-ylmethyl)-1H-indole.

Following this procedure the following compounds were prepared:

A. (R)-3-(N-Benzyloxycarbonylpyrrolidin-2-ylmethyl)-1H-indole

(R)-1-(N-Benzyloxycarbonylpyrrolidin-2-yl)-3-(N-(2-iodophenyl)-N-trifluoroacetyl-amino)propenewas used. Column chromatography afforded the title compound as a clear,pale brown oil: ¹ NMR(CDCl₃) δ8.05 (br s, indole NH), 7.49-7.34 (m, 7H),7.17 (br t, 1H), 7.02 (br s, 1H), 6.95 (br s, 1H), 5.24 (s, 2H),4.28-4.14 (br m, 1H), 3.52-3.41 (m, 2H), 3.28 (br d, 1H), 2.79-2.63 (m,1H), 1.90-1.70 (m, 4H); LRMS (m/z, relative intensity) 334 (10, M+), 204(16), 160 (39), 130 (39), 91 (100).

B.(R)-3-(N-Benzyloxycarbonylpyrrolidin-2-ylmethyl)-5-(methylaminosulfonylmethyl)-1H-indole

(R)-1-(N-Benzyloxycarbonylpyrrolidin-2-yl)-3-(N-(2-bromo-4-methylaminosulfonylmethylphenyl)-N-trifluoroacetylamino)propenewas used. Column chromatography afforded the title compound as anoff-white foam: IR (CHCl₃) 1673, 1410, 1358, 1324, 1118, 1092 cm⁻¹ ;LRMS (m/z, relative intensity) 441 (9, M+), 237 (29), 204 (77), 160(97), 143 (73), 91 (100); HRMS: calculated for C₁₃ H₂₇ N₃ O₄ S:441.1724; found: 441.1704.

C. (R)-3-(N-Benzyloxy-carbonylpyrrolidin-2-ylmethyl-5-cyano-1H-indole

(R)-1-(N-Benzyloxycarbonylpyrrolidin-2-yl)-3-(N-(2-bromo-4-cyanophenyl)-N-trifluoroacetylamino)propenewas used. Column chromatography afforded the title compound as a whitefoam: IR (1% solution in CHCl₃) 2215, 1687 cm⁻¹ ; ¹³ C NMR [Note: due toslow nitrogen inversion two conformers of the products are seen by NMRspectroscopy] (CDCl₃) δ155.1, 137.9, 137.0, 128.8, 128.5, 128.4, 128.0,127.8, 124.9, 124.6, 121.0, 114.0, 113.9, 112.1, 102.3, 67.2, 66.7,58.5, 57.6, 47.0, 46.7, 30.3, 30.0, 29.6, 28.8, 23.6, 22.7. Anal. calcdfor C₂₂ H₂₁ N₃ O₂ •0.25 C₂ H₄ O₂ [acetic acid]: C, 72.17; H, 5.92; N,11.22. Found: C, 72.28; H, 5.76; N, 10.95.

D.(R,S)-3-(N-Benzyloxycarbonylpiperid-2-ylmethyl)-5-(methylaminosulfonylmethyl-1H-indole

(R,S)-1-(N-Benzyloxycarbonylpiperid-2-yl)-3-(N-(2-bromo-4-methylaminosulfonyl-methylphenyl)-N-trifluoroacetylamino)propenewas used. Column chromatography afforded the title compound as anoff-white foam: ¹³ C NMR [Note: due to slow nitrogen inverion twoconformers of the products are seen by NMR spectroscopy] (CHCl₃) δ162.5,136.9, 136.2, 128o4, 127.6, 124.5, 123.3, 120.8, 120.3, 111.5, 66.8,57.4, 39.5, 36.5, 31.4, 29.8, 25.8, 25.5, 18.8; LRMS (m/z, relativeintensity) 445 (5, M+), 361 (4), 238 (40), 218 (80), 174 (100), 143(53); HRMS calculated for C₂₄ H₂₉ N₃ O₄ S: 455.1880; found: 455.1899.

EXAMPLE 8(R)-3-(N-Benzyloxycarbonylpyrrolidin-2-ylmethyl)-5-methoxy-1H-indole

To a stirred mixture of lithium borohydride (0.092 g, 4.22 mmol, 2 eq)in anhydrous tetrahydrofuran (5 mL) at 0° C. was added a solution of the(R)-3-(N-benzyloxycarbonylpyrrolidin-2-ylcarbonyl)-5-methoxy-1H-indole(0.80 g, 2.11 mmol) in anhydrous tetrahydrofuran (8 mL). The resultantmixture was heated at reflux under nitrogen for 1 hour. The reactionmixture was cooled, and water (1 mL) was added carefully, followed byethyl acetate (20 mL). The resultant mixture was stirred at roomtemperature for 30 minutes, dried (MgSO₄), filtered through diatomaceousearth, and the filtrate was evaporated under reduced pressure. Theresidue was column chromatographed using silica gel (approximately 50 g)and elution with ethyl acetate/hexanes [1:1] afforded(R)-3-(N-benzyloxycarbonylpyrrolidin-2-ylmethyl)-5-methoxy-1H-indole asa colorless gum: ¹³ C NMR [Note: due to slow nitrogen inversion twoconformers of the products are seen by NMR spectroscopy] (CDCl₃) δ162.5,136.9, 136.2, 128.4, 127.8, 127.6, 124.5, 123.3, 120.8, 120.3, 111.5,66.8, 57.4, 39.5, 36.5, 31.4, 29.8, 25.8, 25.5, 18.8; LRMS (m/z,relative intensity) 364 (30, M+), 204 (17), 160 (92), 145 (17), 117(13), 91 (100). Anal. calcd for C₂₂ H₂₄ N₂ O₃ •0.5 H₂ O: C, 70.76; H,6.75; N, 7.50. Found: C, 70.70; H, 6.94; N, 7.15.

EXAMPLE 9 General Procedure for the Formation of1-(N-Benzyloxy-carbonylpyrrolidin-2-yl)-3-(N-(2-halophenyl)-N-trifluoroacetylamino)propenesand1-(N-Benzyloxycarbonylpiperid-2-yl)-3-(N-(2-halophenyl)-N-trifluoroacetylamino)propenesfrom the Mitsunobu Coupling of 2-Halo-N-trifluoroacetylanilines with1-(N-Benzyloxycarbonylpyrrolidin-2-y1)-3-hydroxypropene or1-(N-Benzyloxycarbonyl-piperid-2-yl)-3-hydroxypropene

To a stirred mixture of1-(N-benzyloxycarbonylpyrrolidin-2-yl)-3-hydroxypropene or1-(N-benzyloxycarbonylpiperid-2-yl)-3-hydroxy-propene (R, or S, orracemate 2.00 mmol), the 2-halo-N-trifluoroacetylaniline (2.5 mmol, 1.25eq), and triphenylphosphine (0.655 g, 2.50 mmol, 1.25 eq) in anhydroustetrahydrofuran at 0° C. under a nitrogen atmosphere was added diethylazodicarboxylate (0.39 mL, 2.48 mmol, 1.25 eq) dropwise. The reactionsolution was slowly warmed to 25° C. over the course of 2 hours, andthen stirred at 25° C. under a nitrogen atmosphere for an additional 12hours. The resulting reaction solution was evaporated under reducedpressure, and the residue was column chromatographed using silica gel(approximately 50 g) and elution with either a diethyl ether gradient inhexanes or an ethyl acetate gradient in hexanes to afford thecorresponding1-(N-benzyloxycarbonylpyrrolidin-2-yl)-3-(N-(2-halophenyl)-N-trifluoroacetylamino)propeneor1-(N-benzyloxycarbonylpiperid-2-yl)-3-(N-(2-halophenyl)-N-trifluoroacetylamino)propene.

Following this procedure the following compounds were prepared:

A.(R)-1-(N-Benzyloxycarbonylpyrrolidin-2-yl)-3-(N-(2-iodophenyl)-N-trifluoroacetylamino)propene

(R)-1-(N-Benzyloxycarbonylpyrrolidin-2-yl)-3-hydroxypropene and2-iodo-N-trifluoro-acetylaniline were used. Column chromatographyafforded the title compound as a clear, colorless oil: ¹ H NMR (CDCl₃)δ7.88 (br d, 1H), 7.43-6.89 (m, 10H), 5.70-5.35 (m, 2H), 5.13 (br s,2H), 5.00-4.75 (m, 1H), 4.40-4.29 (m, 1H), 3.60-3.42 (m, 3H), 2.05-1.45(m, 4H); LRMS (FAB, m/z, relative intensity) 559 (100, [MH+]), 515 (52),451 (15), 244 (7).

B.(R)-1-(N-Benzyloxycarbonylpyrrolidin-2-yl)-3-(N-(2-bromo-4-methylaminosulfonylmethylphenyl)-N-trifluoroacetylamino)propene

(R)-1-(N-Benzyloxycarbonylpyrrolidin-2-yl)-3-hydroxypropene and2-bromo-4-methylaminosulfonylmethyl-N-trifluoroacetylaniline were used.Column chromatography using elution with 4% acetone in methylenechloride afforded the title compound as a white foam (44%): FAB LRMS(m/z, relative intensity) 620 ([MH+ with ⁸¹ Br], 618 ([MH+ with ⁷⁹ Br],98), 576 (50), 574 (63), 512 (17), 484 (33).

C.(R)-1-(N-Benzyloxycarbonylpyrrolidin-2-yl)-3-(-N-(2-bromo-4-cyanophenyl)-N-trifluoroacetylamino)propene

(R)-1-(N-Benzyloxycarbonylpyrrolidin-2-yl)-3-hydroxypropene and2-bromo-4-cyano-N-trifluoroacetylaniline were used. Columnchromatography using elution with a gradient of diethyl ether (5%-100%)in methylene chloride afforded the title compound as a clear, colorlessoil: IR (CHCl₃) 2231, 1702, 1157 cm⁻¹ ; LRMS (m/z, relative intensity)537 ([MH+ with ⁸¹ Br], 13), 535 ([MH+ with ⁷⁹ Br], 13), 402 (29), 400(30), 294 (55), 292 (57), 244 (80), 213 (89), 91 (100); Anal. calcd forC₂₄ BrF₃ H₂₁ N₃ O₃ •0.2 H₂ O: C, 53,39; H, 3.99; N, 7.78. Found: C,53.25; H, 3.95; N, 7.98.

D.(R,S)-1-(N-Benzyloxycarbonylpiperid-2-yl)-3-(N-(2-bromo-4-methylaminosulfonylmethylphenyl)-N-trifluoroacetylamino)propene

(R,S)-1-(N-Benzyloxycarbonylpiperid-2-yl)-3-hydroxypropene and2-bromo-4-methylaminosulfonylmethyl-N-trifluoroacetylaniline were used.Column chromatography using elution with 20% acetonitrile in methylenechloride afforded the title compound as a white foam: FAB LRMS (m/z,relative intensity) 634 ([MH+ with ⁸¹ Br], 26), 632 ([MH+ with ⁷⁹ Br],22), 590 (35), 588 (43), 401 (33), 327 (48), 281 (75), 207 (90), 147(100); FAB HRMS: calculated for C₂₆ H₂₉ BrF₃ N₃ O₅ S•[H+] 632.1043,found 632.1047 [for ⁷⁹ Br and ³² S].

EXAMPLE 10 General Synthesis of 2-Halo-N-trifluoroacetylanilines fromReaction of 2-Haloanilines and Trifluoroacetic Anhydride

To a stirred solution of the 2-haloaniline (2.00 mmol) and pyridine(0.18 mL, 2.22 mmol, 1.1 eq) in anhydrous methylene chloride (10 mL) at0° C. under a nitrogen atmosphere was added dropwise trifluoroaceticanhydride (0.31 mL, 2.19 mmol, 1.1 eq). The resultant reaction mixturewas stirred at 0° C. under a nitrogen atmosphere for 3 hours. Asaturated solution of sodium hydrogen carbonate was added (15 mL), andthis aqueous mixture was extracted with ethyl acetate (3×15 mL). Theextracts were combined, dried (MgSO₄), and evaporated under reducedpressure. The residue was column chromatographed using silica gel(approximately 50 g) and elution with an ethyl acetate gradient inhexanes to afford the corresponding 2-halo-N-trifluoroacetylaniline.

Following this procedure the following compounds were prepared:

A. 2-Iodo-N-trifluoroacetylaniline

2-Iodoaniline was used. Evaporation of the ethyl acetate extractsafforded the title compound directly as a white solid: mp, 105.0°-106.5°C.; FAB LRMS (m/z relative intensity) 316 ([MH+], 8), 155 (80), 135(26), 119 (100); ¹³ C NMR (acetone-d₆) δ206.2, 140.4, 130.2, 130.1,128.2.

B. 2-Bromo-4-methylaminosulfonylmethyl-N-trifluoroacetylaniline

2-Bromo-4-methylaminosulfonylmethylaniline was used. Evaporation of theethyl acetate extracts afforded the title compound directly as a whitesolid: mp, 164.0°-166.0° C. Anal. calcd for C₁₀ H₁₀ BrF₃ N₂ O₃ S: C,32.02; H, 2.69; N, 7.47. Found: C, 32.18; H, 2.67; N, 7.30.

C. 2-Bromo-4-cyano-N-trifluoroacetylaniline

2-Bromo-4-aminocarbonylaniline was used. Dehydration of the carboxamidealso occurred in this reaction. Column chromatography using ethylacetate/hexanes afforded the title compound as a white solid: mp,125°-130° C.; ¹ H NMR (DMSO-d₆) δ11.6 (br s, NH), 8.37 (d, J=1.8 Hz,1H), 7.96 (dd, J=1.8 and 8.2 Hz, 1H), 7.71 (d, J=8.2 Hz, 1H).

EXAMPLE 11 General Procedure for the Bromination of Anilines to Form2-Bromoanilines

To a stirred solution of the aniline (2.00 mmol) and sodium hydrogencarbonate (0.21 g, 2.50 mmol, 1.25 eq) in methanol (10 mL) at 0° C. wasadded dropwise bromine (0.113 mL, 2.19 mmol, 1.1 eq). The resultingreaction mixture was then stirred at 25° C. for 30 minutes. The reactionmixture was then evaporated under reduced pressure, and the residue wasplaced in a saturated solution of sodium hydrogen carbonate (10 mL).This aqueous mixture was extracted with ethyl acetate (3×15 mL). Theextracts were combined, dried (MgSO₄), and evaporated under reducedpressure. The residue was column chromatographed using silica gel(approximately 50 g) and elution with an appropriate solvent system toafford the corresponding 2-bromoaniline.

Following this procedure the following compounds were prepared:

A. 2-Bromo-4-methylaminosulfonylmethylaniline

4-Methylaminosulfonylmethylaniline (M. D. Dowle, et al. Eur. Pat. Appl.EP225,726) was used. Column chromatography using elution with 40% ethylacetate in hexanes afforded the title compound as a white solid: mp,104.0°-107.0° C. Anal. calcd for C₈ H₁₁ BrN₂ O₂ S: C, 34.42; H, 3.97; N,10.04. Found: C, 34.66; H, 3.96; N, 9.96.

B. 4-Aminocarbonyl-2-bromoaniline

4-Aminobenzamide was used. Column Chromatography using elution with aethyl acetate gradient (25-50%) in methylene chloride afforded the titlecompound as a white solid: mp, 144.5°-146.0° C.; ¹ H NMR (DMSO-d₆) δ7.93(d, J=2.0 Hz, 1H), 7.70 (br s, amide NH), 7.62 (dd, J=2.0 and 8.5 Hz,1H), 7.05 (br s, amide NH), 6.77 (d, J=8.5 Hz, 1H), 5.85 (s, anilineNH₂).

EXAMPLE 12 1-(N-Benzyloxycarbonylpyrrolidin-2-yl)-3-hydroxypropene or1-(N-Benzyloxycarbonylpiperid-2-yl)-3-hydroxypropene

To a stirred solution of either ethyl3-(N-benzyloxycarbonylpyrrolidin-2-yl)-2-propenoate orethyl-3-(N-benzyloxycarbonylpiperid-2-yl)-2-propenoate (R, or S, orracemate, 10.00 mmol) in anhydrous tetrahydrofuran (75 mL) at -78° C.under nitrogen was added dropwise a solution of diisobutylaluminiumhydride (1.0M in hexanes, 12.0 mL, 22.0 mmol, 2.2 eq). The resultingsolution was stirred at -78° C. under nitrogen for 30 minutes. Thereaction solution was then allowed to warmed to room temperature overthe course of 2 hours. A saturated solution of sodium hydrogen carbonate(50 mL) was added, and the aqueous mixture was extracted with ethylacetate (3×50 mL). The extracts were combined, dried (MgSO₄), andevaporated under reduced pressure. Column chromatography of the residuewith diethyl ether/hexanes [1:1] afforded either1-(N-benzyloxycarbonylpyrrolidin-2-yl)-3-hydroxypropene or1-(N-benzyloxycarbonyl-piperid-2-yl)-3-hydroxypropene.

Following the procedure the following compounds were prepared:

A. (R)-1-(N-Benzyloxycarbonylpyrrolidin-2-yl)-3-hydroxypropene

(R)-Ethyl 3-(N-benzyloxycarbonylpyrrolidin-2-yl)-2-propenoate was used.Chromatography of the extraction residue afforded the title compound asa clear, colorless oil: ¹ H NMR (CDCl₃) δ7.40-7.25 (m, 5H), 5.75-5.53(m, 2H), 5.20-5.00 (m, 2H), 4.38 (br m, 1H), 4.06 (br d, J=13.7 Hz, 2H),3.45 (br t, J=7 0 Hz, 1H), 2.03-1.68 (m, 4H); [α]²⁵ _(D) =+34° (MeOH,c=1.0); HRMS: calculated for C₁₅ H₁₉ NO₃ 261. 1365, found 261.1356.

B. (R,S)-1-(N-Benzyloxycarbonylpiperid-2-yl)-3-hydroxypropene

(R,S)-Ethyl 3-(N-benzyloxycarbonylpiperid-2-y1)-2-propenoate was used.Chromatography of the extraction residue afforded the title compound asa clear, colorless oil: LRMS (m/z, relative intensity) 257 (3), 212(12), 193 (8), 175 (65), 173 (100), 145 (27), 109 (24), 91 (87); ¹ H NMR(CDCl₃) δ7.40-7.20 (m, 5H), 5.70-5.61 (m, 2H), 5.14 (d, J=17.6 Hz, 1H),5.10 (d, J=17.5 Hz, 1H), 4.88 (br m, 1H), 4.14-4.00 (m, 3H), 2.91 (br t,J=12.7 Hz, 1H), 1.78-1.47 (m, 6H). Anal. calcd for C₁₆ H₂₁ NO₃ •0.1 H₂O: C, 69.34; H, 7.71; N, 5.05. Found: 69.38; H, 7.84; N, 5.16.

EXAMPLE 13 Synthesis of Ethyl3-(N-Benzyloxycarbonylpyrrolidin-2-yl)-2-propenoate or Ethyl3-(N-Benzyloxycarbonylpiperid-2-yl)-2-propenoate

To a stirred solution of N-carbobenzyloxypyrrolidine-2-carboxaldehyde orN-carbobenzyloxypiperidine-2-carboxaldehyde (5.00 mmol) [S. Kiyooka, etal., J. Org. Chem., 5409 (1989) and y. Hamada, et al., Chem. Pharm.Bull., 1921 (1982)] in anhydrous tetrahydrofuran at -78° C. was added(carbethoxymethylene)triphenylphosphorane (2.09 g, 6.00 mmol. 1.2 eq) asa solid portionwise. The resulting reaction mixture was stirred at roomtemperature under nitrogen for 2 hours, and then heated at reflux undernitrogen for 1 hour. The reaction mixture was evaporated under reducedpressure and the residue was column chromatographed using silica gel(approximately 100 g) and elution with 20% diethyl ether in hexanesafforded either ethyl3-(N-benzyloxycarbonylpyrrolidin-2-yl)-2-propenoate or ethyl3-(N-benzyloxycarbonylpiperid-2-yl)-2-propenoate.

A. (R)-Ethyl 3-(N-Benzyloxycarbonylpyrrolidin-2-yl)-2-propenoate

(R)-N-Carbobenzyloxypyrrolidine-2-carboxaldehyde was used.Chromatography as described above afforded the title compound as aclear, colorless oil: ¹ NMR (CDCl₃ -d₆) δ7.34-7.25 (m, 5H), 6.89-6.76(m, 1H), 5.88-5.74 (m, 1H), 5.18-5.05 (m, 2H), 4.60-4.43 (m, 1H), 4.17(q, J=7.1 Hz, 2H), 3.55-3.40 (m, 2H), 2.11-2.00 (m, 1H), 1.90-1.75 (m,3H), 1.28 (t, J=7.1 Hz, 3H); ¹³ C NMR (CDCl₃) [Note: due to slownitrogen inversion two conformers of the products are seen by NMRspectroscopy] δ166.3, 154.7, 147.9, 147.4, 136.6, 128.4, 127.9, 120.9,66.9, 65.8, 60.4, 58.1, 57.7, 46.8, 46.4, 31.6, 30.8, 23.6, 22.8, 22.6,15.3, 14.2.

B. (R,S)-Ethyl 3-(N-Benzyloxycarbonylpiperid-2-yl)-2-propenoate

(R,S)-N-Carbobenzyloxypiperidine-2-carboxaldehyde was used.Chromatography as described above afforded the title compound as aclear, colorless oil: ¹ H NMR (CDCl₃ -d₆) δ7.36-7.27 (m, 5H), 6.85 (dd,J=4.4 and 16.3 Hz, 1H), 5.80 (dd, J-2.4 and 16.3 Hz, 1H), 5.11 (s, 2H),5.01 (br m, 1H), 4.17 (q, J=6.7 Hz, 2H), 4.05 (br d, J=12.6 Hz, 1H),2.87 (br t, 1H), 1.80-1.35 (m, 6H), 1.27 (t, J=6.6 Hz, 3H); FAB LRMS(m/z, relative intensity) 318 ([MH+], 100), 274 (86), 228 (14), 210(21), 182 (43), 138 (32).

EXAMPLE 14

(R)-5-Amino-3-(N-methylpyrrolidin-2ylmethyl)indole

A mixture of (R)-5-dibenzylamino-3-(N-methylpyrrolidin-2-ylmethyl)indole(1.08 g, 2.64 mmol) and palladium [II] hydroxide on carbon (0.6 g) inabsolute ethanol (25 mL) was shaken under a hydrogen atmoshpere (3 atm)at 40° C. for 4 hours. The resulting mixture was filtered throughdiatmaceous earth, and the filtrate was evaporated under pressure toafford the title compound (0.60 g, 2.62 mmol, 99%) as a white foam: ¹ HNMR (DMSO-d₆) δ10.65 (br s, NH), 7.14 (d, J=2.2 Hz, 1H), 7.12 (d, -J=8.6Hz, 1H), 6.85 (d, J=1.6 Hz, 1H), 6.60 (dd, J=2.0 and 8.6 Hz, 1H),3.63-2.83 (m, 7H), 2.78 (s, 3H), 2.05-1.67 (m, 4H); [α]²⁵ _(D) =+9°(MeOH, c=1.0); HRMS: calculated for C₁₄ H₁₉ N₃ : 229.1575; found229.1593.

EXAMPLE 15 General Synthesis of5-Carbonylamino-3-(N-methyl-pyrrolidin-2-ylmethyl)-1H-indoles and5-Sulfonylamino-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indoles

To a stirred solution of (R)-5-amino-3-(N-methylpyrrolidin-2-ylmethyl)indole (0. 229 g, 1.00 mmol) and triethylamine (0.21 mL, 1.5 mmol, 1.5eq) in anhydrous acetonitrile (3 mL) at 0° C. under nitrogen was addedthe appropriate carbonyl chloride or sulfonyl chloride (1.5 mmol, 1.5eq). The resulting reaction mixture was stirred at room temperature for12 hours. The reaction mixture was then evaporated under reducedpressure, and the residue was column chromatographed using silica gel(approximately 25 g) and elution with an appropriate solvent systemafforded the appropriate5-carbonylamino-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole or5-sulfonylamino-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole.

Following this procedure the following compounds were prepared:

A.(R)-5-Benzyloxycarbonylamino-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole

Benzyl chloroformate was used. Column chromatography using elution withtriethylamine/acetone/ethyl acetate [2:10:88] afforded the titlecompound as an off-white foam: ¹³ C NMR (CDCl₃) δ163.3, 136.4, 133.6,129.8, 128.6, 128.2, 127.9, 126.0, 123.2, 113.8, 111.4, 110.1, 66.8,66.5, 57.5, 40.8, 31.5, 29.8, 21.8; LRMS (m/z, relative intensity) 363(M+, 12), 279 (7), 184 (7), 171 (33), 108 (100); HRMS: calculated forC₂₂ H₂₅ N₃ O₂ 363.1949, found 363.1926. Anal. calcd for C₂₂ H₂₅ N₃ O₂•0.4 C₄ H₈ O₄ [ethyl acetate]: C, 71.09; H, 7.13; N, 10.54. Found: C,70.82; H, 7.03; N, 10.58.

B. (R )-3-(N-Methylpyrrolidin-2-ylmethyl)-5-methylsulfonamido-1H-indole

Methanesulfonyl chloride was used. Column chromatography using elutionwith triethylamine/acetone/ethyl acetate [1:3:6] afforded the titlecompound as a white foam: ¹³ C NMR (CDCl₃) δ134.9, 128.3, 128.2, 123.6,119,3, 115.0, 113.9, 112.0, 66.7, 57.3, 40.7, 38.7, 31.3, 29.4, 21.7;HRMS: calculated for C₁₅ H₂₁ N₃ O₂ S [with ³² S] 307.1356, found307.1323.

C. (R)-5-Acetylamino-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole

Acetyl chloride was used. Column chromatography using elution withtriethylamine/acetone/ethyl acetate [1:3:6] afforded the title compoundas a white foam: ¹³ C NMR (acetone-d₆) δ168.3, 134.4, 132.2, 128.7,124.1, 115.7, 13.8, 111.6, 110.2, 67.3, 58.0, 40.9, 31.9, 30.5, 24.1,2.5; LRMS (m/z, relative intensity) 271 (M+, 39), 241 (4), 207 (5), 187(20), 144 (20), 84 (100); HRMS: calculated for C₁₆ H₂₁ N₃ O 271.1686,found 271.1693. Anal. calcd for C₁₆ H₂₁ N₃ O•1.15 H₂ O: C, 65.80; H,8.04; N, 14.39. Found: C, 5.99; H, 7.90; N, 13.99.

D.(R)-5-N,N-Dimethylaminocarbonylamino-3-(N-methyl-pyrrolidin-2-ylmethyl)-1H-indole

Dimethylcarbamyl chloride was used. Column chromatography using elutionwith methylene chloride/methanol/ammonium hydroxide [9:1:0.1] affordedthe title compound as an off white foam: ¹ H NMR (CDCl₃) δ8.95 (br s,1H), 7.49 (br s, 1H), 7.15-7.06 (m, 2H), 6.82 (d, J=1.9 Hz, 1H), 6.44(br s, 1H), 3.12-3.05 (m, 2H), 3.00 (s, 6H), 2.58-2.40 (m, 2H), 2.40 (s,3H), 2.18 (br q, J=8.1 Hz, 1H), 1.83-1.47 (m, 4H); ¹³ C NMR (CDCl₃)δ157.2, 133.8, 130.5, 127.7, 123.2, 117.8, 113.0, 112.0, 111.3, 66.5,57.4, 40.6, 36.4, 31.4, 29.8, 21.7; LRMS (m/z, relative intensity) 300(M+, 50), 217 (10), 171 (20), 84 (100); HRMS: calculated for C₁₇ H₂₄ N₄O 300.1952, found 300.1957.

E.(R)-5-Trifluoroacetylamino-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole

Trifluoroacetic anhydride was used. Column chromatography using elutionwith methylene chloride/methanol/ammonium hydroxide [9:1:0-0.1] affordedthe title compound as an off white foam: ¹ H NMR (CDCl₃) δ8.99 (br s,1H), 7.80 (br s, 1H), 7.27-7.19 (m, 2H), 6.95 (d, -J=l.4 Hz, 1H0,3.16-3.08 (m, 2H), 2.58 (dd, J=9.4 and 13.5 Hz, 1H). 2.57-2.43 (m, 1H),2.43 (m, 1H), 2.43 (s, 3H), 2.22 (dd, J=9.2 and 17.5 Hz, 1H), 1.85-1.46(m, 4H); ¹³ C NMR (CDCl₃) δ134.5, 127.7, 126.9, 123.8, 116.1, 113.9,111.9, 111.6, 104.1, 66.6, 57.3, 40.6, 31.3, 29.5, 21.7; HRMS:calculated for C₁₆ H₁₈ F₃ N₃ O 325.1403, found 325.1378.

EXAMPLE 16(R)-3-(N-Methylpyrrolidin-2-ylmethyl)-5-(2-methylsulfonamidomethyl)-1H-indole

To a stirred mixture of(R)-5-aminomethyl-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole (0.113 g,0.46 mmol) and pyridine (50 μL, 0.93 mmol, 2.0 eq) in a solution ofdimethylformamide and acetonitrile (1:3, respectively, 2 mL total) at 0°C. under nitrogen was added methanesulfonyl chloride dropwise (44 μL,0.56 mmol, 1.3 eq). The resulting reaction solution was stirred at roomtemperature under nitrogen for 1 hour, and then it was evaporated underreduced pressure. The residual oil was column chromatographed usingsilica gel (6 g) and elution with methylene chloride/methanol/ammoniumhydroxide [9:1:0.1] afforded the title compound (0.044 g, 0.14 mmol,30%) as a white foam: ¹ H NMR (CDCl₃) δ8.25 (br s, NH), 7.54 (br s, 1H),7.35 (d, J=8.4 Hz, 1H), 7.17 (dd, J=1.6 and 8.4 Hz, 1H), 7.06 (d, J=l.8Hz, 1H), 4.78 (br s, NH), 4.42 (s, 2H), 3.20-3.12 (m, 2H), 2.87 (s, 3H),2.64 (dd, J=9.4 and 13.9 Hz, 1H). 2.54-2.43 (m, 1H), 2.47 (s, 3H), 2.25(dd, J=9.3 and 17.3, 1H), 1.86-1.52 (m, 4H); ¹³ C NMR (CDCl₃) δ135.8,127.8, 127.3, 123.0, 122.0, 118.5, 113.7, 111.6, 66.7, 57.4, 47.9, 40.9,40.7, 31.3, 29.5, 21.7; LRMS (m/z relative intensity) 321 (28), 320 (M+,26), 237 (51), 157 (100), 143 (64), 129 (78); HRMS: calculated for C₁₆H₂₂ N₃ O₂ S 320.1435, found 320.1453.

EXAMPLE 17 General Synthesis of Allylsulphonamides

A. Allylsulphonamide

The title compound was prepared by the method of M. A. Belous and I. Ya.Postouski, Zhur. Obschei. Khim., 1950, 20, 1701.

B. N-Methylallylsulphonamide

The title compound was prepared by an analogous procedure to above byusing methylamine instead of ammonia. Anal. Calcd for C₅ H₁₁ NO₂ S;C,40.25; H,7.43; N,9.38. Found: C,40.51; H,7.37; N,9.70.

EXAMPLE 18 Preparation of Ethylallylsulphone

The title compound was prepared by the method of R. J. Palmer and C. J.M. Stirling., J. Amer. Chem. Soc., 1980, 102, 7888.

EXAMPLE 19 General Synthesis of Vinyl Sulphonamides

Where the required vinylsulphonamide was not commercially available,they were prepared by the following procedure based on the proceduredescribed in Zhur. Obschei. Khim., 1959, 29, 1494.

A. N,N-Dimethylvinylsulphonamide

To a stirred solution of chloroethylsulphonyl chloride (25 g, 153 mmol)in dry diethyl ether (150 mL) at -10° C., was added dropwise a solutionof dimethylamine (30.5 mL, 460 mmol) in dry diethyl ether (100 mL) over5 minutes. After stirring for 90 minutes at -10° C. the solution wasfiltered and evaporated in vacuo. The residue was distilled to give thetitle compound (9.5 g, 46%): b.p. 120°-122° C. (20 mmHg). Anal. Calcdfor C₄ H₉ NO₂ S: C,35.54; H,6.71; N,10.36%. Found: C,35.36; H,6.37;N,10.19.

B. The following examples were prepared by the general procedure above,using the appropriate amine starting material. Purification was bydistillation or column chromatography.

    ______________________________________                                        R.sub.2 NSO.sub.2CHCH.sub.2                                                                    Analysis %                                                                    (Theoretical in brackets)                                    R.sub.2 N Isolated Form                                                                              C        H     N                                       ______________________________________                                        MeNH      Oil b.p. 93-5° C.                                                                   Literature compound                                              (0.05 mm Hg) U.S. 3,761,473                                          ##STR30##                                                                              Oil          47.97 (47.97                                                                           7.41 7.48                                                                           7.81 7.99)                               ##STR31##                                                                              Oil          44.73 (44.70                                                                           6.80 6.88                                                                           8.62 8.69)                              nPr.sub.2 N                                                                             Oil          50.37    8.79  7.68                                                           (50.23   8.96  7.32)                                   nPrNH     Oil          40.22    7.35  9.1                                                            (40.24   7.43  9.39)                                    ##STR32##                                                                              Oil          40.51 (40.79                                                                           5.85 6.16                                                                           9.35 9.52)                              iPrNH     Oil          40.42    7.33  9.30                                                           (40.25   7.43  9.39)                                   ______________________________________                                    

    ______________________________________                                                           Analysis %                                                                    (Theoretical                                                                  in brackets)                                               R         Isolated Form  C       H                                            ______________________________________                                        RS--CH.sub.2 CH.sub.2 --OH                                                    nPr       Oil  1/16 EtOAc                                                                              48.68   9.79                                                    1/5 H.sub.2 O (48.76  10.06)                                       nBu       Oil            T.I.c - Rf. 0.26                                                              (SiO.sub.2, Ether/Hexane                                                      1:1)                                                 RS--CH.sub.2 CH.sub.2 --Cl                                                    nPr       Oil  1/5 H.sub.2 O  1/30                                                                     41.63   7.60                                                   CH.sub.2 Cl.sub.2                                                                            (41.65  7.69)                                        nBu       Oil 1.0 H.sub.2 O                                                                            42.31   7.84                                                                  (42.21  8.27)                                        RSO.sub.2 --CH.sub.2 CH.sub.2 Cl                                              nPr       Oil            34.75   6.68                                                                  (35.19  6.50)                                        nBu       Oil  1/15 CH.sub.2 Cl.sub.2                                                                  38.41   7.01                                                                  (38.27  6.95)                                        RSO.sub.2 --CH═CH.sub.2                                                   nBu       Oil            48.95   8.07                                                                  (48.62  8.16)                                        ______________________________________                                    

EXAMPLE 21 General Synthesis of indoles with 5-alkenyl substituents

A.(R)-5-trans-(2-N,N-Dimethylaminocarbonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole

A mixture of N,N-dimethylacrylamide (134 μL, 1.3 mmol),tri-o-tolylphosphine (91 mg, 0.3 mmol), palladium (II) acetate (15 mg,0.07 mmol), triethylamine (280 μL, 2 mmol) and(R)-5-bromo-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole was dissolved inanhydrous acetonitrile (5 mL) and refluxed for 24 hours under nitrogen.The reaction was partitioned between ethyl acetate and aqueous sodiumcarbonate. The dried (Na₂ SO₄) organic phase was evaporated and theresidue purified by column chromatography on silica gel, eluting withCH₂ Cl₂ : MeOH: NH₄ OH 96:3.5:0.5 to afford the title compound as awhite foam (145 mg, 47%). Anal. Calcd for C₁₉ H₂₅ N₃ O•1/9 CH₂ Cl₂ : C,71.56; H, 7.87; N, 13.10 %. Found: C,71.29; H,8.15; N,13.05.

B. The following examples were prepared using the above procedure withthe appropriate alkene starting material (available commercially, orprepared by routes outlined in this patent).

    __________________________________________________________________________     ##STR33##                                                                                             Analysis %  [α].sub.D.sup.25                                            (Theoretical in brackets)                                                                 (c = 0.1                                 R.sup.2     Isolated Form                                                                              C   H   N   MeOH)                                    __________________________________________________________________________    MeSO.sub.2 CHCH                                                                           Foam  3/10 CH.sub.2 Cl.sub.2                                                               60.45                                                                             6.43                                                                              8.33                                                                  (60.42                                                                            6.62                                                                              8.15)                                        PhSOCHCH    Foam  1/10 CH.sub.2 Cl.sub.2                                                               68.04                                                                             6.27                                                                              6.99                                                                  (68.24                                                                            6.27                                                                              7.20)                                        NH.sub.2 SO.sub.2 CHCH                                                                    Foam  1/3 MeOH  1/3 H.sub.2 O                                                              58.56                                                                             6.80                                                                              12.19                                                                 (58.39                                                                            6.85                                                                              12.51)                                       EtSOCHCH    Foam  1/20 CH.sub.2 Cl.sub.2  1/4 H.sub.2 O                                                66.70                                                                             7.35                                                                              8.64                                                                  (66.66                                                                            7.62                                                                              8.62)                                         ##STR34##  Foam  1/8 CH.sub.2 Cl.sub.2  1/2 H.sub.2 O                                                 61.74 (61.49                                                                      6.93 7.22                                                                         10.53 10.69)                                 nBuSO.sub.2 CHCH                                                                          Foam  1/4 CH.sub.2 Cl.sub.2                                                                63.56                                                                             7.77                                                                              7.22                                                      1/10 EtOH   (63.59                                                                            7.57                                                                              7.25)                                        Me.sub.2 NSO.sub.2 CHCH                                                                   Foam  1/3 H.sub.2 O                                                                        61.14                                                                             7.06                                                                              11.57                                                                 (61.19                                                                            7.27                                                                              11.89)                                        ##STR35##  Foam  1/2 CH.sub.2 Cl.sub.2  1/4 H.sub.2 O                                                 59.64 (59.83                                                                      6.82 7.07                                                                         9.83 9.67)                                   nPr.sub.2 NSO.sub.2 CHCH                                                                  Foam 1.0 H.sub.2 O  1/10 CH.sub.2 Cl.sub.2                                                 61.48                                                                             7.76                                                                              9.69                                                                  (61.72                                                                            8.25                                                                              9.77)                                        nPrNHSO.sub.2 CHCH                                                                        Foam  1/10 CH.sub.2 Cl.sub.2  1/3 H.sub.2 O                                                61.07                                                                             7.12                                                                              10.91                                                                 (61.01                                                                            7.49                                                                              11.18)                                        ##STR36##  Foam  1/3 CH.sub.2 Cl.sub.2 I H.sub.2 O                                                    56.83 (56.39                                                                      6.40 6.87                                                                         10.36 10.36)                                                                      +34°                              iPrNHSO.sub.2 CHCH                                                                        Foam  1/6 CH.sub.2 Cl.sub.2                                                                61.03                                                                             7.42                                                                              11.17                                                                             +30°                                                       (61.27                                                                            7.33                                                                              11.19)                                       PhSO.sub.2 CH.sub.2 CHCH                                                                  Foam  1/6 CH.sub.2 Cl.sub.2                                                                68.21                                                                             6.81                                                                              7.15                                                                  (68.27                                                                            6.50                                                                              6.87)                                        Me.sub.2 NSO.sub.2 CH.sub.2 CHCH                                                          Foam  1/20 CH.sub.2 Cl.sub.2                                                               62.54                                                                             7.50                                                                              11.21                                                                 (62.55                                                                            7.46                                                                              11.48)                                       NH.sub.2 SO.sub.2 CH.sub.2 CHCH                                                           Foam 0.1 CH.sub.2 Cl.sub.2                                                                 58.50                                                                             6.93                                                                              11.22                                                    1.0 MeOH     (58.13                                                                            7.30                                                                              11.24)                                       EtSO.sub.2 CH.sub.2 CHCH                                                                  Foam         65.56                                                                             7.47                                                                              8.00                                                                  (65.86                                                                            7.56                                                                              8.08)                                        PhCONHCH.sub.2 CHCH                                                                       Foam 0.1 CH,Cl.sub.2                                                                       75.69                                                                             6.97                                                                              10.76                                                                             +70°                                                       (75.78                                                                            7.18                                                                              11.00)                                       MeSO.sub.2 NHCH.sub.2 CHCH                                                                Foam 0.1 CH.sub.2 Cl.sub.2                                                                 61.05                                                                             7.31                                                                              11.12                                                                 (61.07                                                                            7.14                                                                              11.80)                                       __________________________________________________________________________

C) The following compounds could be prepared by the procedure a) abovebut using the corresponding beta-chloroethylsulphone as startingmaterial instead of an alkene. These reactions were preferably carriedout in the presence of 3-6 equivalents of triethylamine.

    __________________________________________________________________________     ##STR37##                                                                                              Analysis %                                                                    (Theoretical in brackets)                                                                 [α].sub.D.sup.25                  R.sup.2         Isolated Form                                                                           C   H   N   (c = 0.1 MeOH)                          __________________________________________________________________________    nPrSO.sub.2 CHCH                                                                              Foam  1/8 CH.sub.2 Cl.sub.2                                                             62.93                                                                             7.15                                                                              7.71                                                         1/3 H.sub.2 O                                                                          (63.25                                                                            7.47                                                                              7.71)                                        ##STR38##      Foam 0.15 CH.sub.2 Cl.sub.2                                                             62.22 (62.20                                                                      5.37 5.49                                                                         6.52 6.55)                                                                        +48°                             __________________________________________________________________________

EXAMPLE 22 General Procedure for Hydrogenation of 5-alkenylindoles

A typical procedure is as follows:

A.(R)-5-(2-Aminosulphonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole

(R)-5-(2-Aminosulphonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole(157 mg, 0.5 mmol) was dissolved in absolute ethanol (10 mL) and addedto a solution of ethanolic hydrogen chloride (25 ml) (prepared fromacetyl chloride (38 μL, 0.53 mmol) and absolute ethanol (25 mL)). 10%palladium-on-carbon (125 mg) was added. This solution was hydrogenatedunder a hydrogen atmosphere (15 p.s.i.) at room temperature for 18hours. The resultant reaction mixture was filtered through diatomaceousearth (Celite trademark or Arbacell-trademark)) washed with absoluteethanol and the combined filtrates evaporated in vacuo. The residue waspurified by column chromatography on silica gel, eluting with a gradientsolvent mixture up to CH₂ Cl₂ : MeOH:NH₄ OH 93:7:1 to give the titlecompound as a colourless oil (80 mg, 51%). Anal. Calcd for C₁₆ H₂₃ N₃ O₂S•1/4 MeOH. 1/3 H₂ O: C,58.21; H,7.36; N,12.54. Found: C,58.60; H,7.40;N,12.57. [α]²⁵ _(D) =+69° (c=0.1, MeOH).

B. The following examples were prepared by an analogous procedure to a)above.

    __________________________________________________________________________     ##STR39##                                                                                          Analysis %                                                                    (Theoritical in brackets)                                                                 [α].sub.D.sup.25                      R.sup.2     Isolated Form                                                                           C   H   N   (c = 0.1 MeOH)                              __________________________________________________________________________    Me.sub.2 NSO.sub.2 CH.sub.2 CH.sub.2                                                      Oil  1/20 CH.sub.2 Cl.sub.2                                                             61.52                                                                             7.40                                                                              11.49                                                                             +48°                                                       (61.31                                                                            7.67                                                                              11.89)                                          Me.sub.2 NCOCH.sub.2 CH.sub.2                                                             Oil  1/10 CH.sub.2 Cl.sub.2                                                             70.96                                                                             8.52                                                                              12.84                                                                             +76.2°                                                     (71.29                                                                            8.46                                                                              13.06)                                          MeSO.sub.2 CH.sub.2 CH.sub.2                                                              Gum  1/4 H.sub.2 O                                                                      62.76                                                                             7.29                                                                              8.41                                                                              +83°                                                       (62.83                                                                            7.60                                                                              8.62)                                           EtSOCH.sub.2 CH.sub.2                                                                     Oil       61.39                                                                             7.69                                                                              8.16                                                                  (61.27                                                                            8.03                                                                              7.83)                                            ##STR40##  Foam  2/3 H.sub.2 O                                                                     62.73 (62.81                                                                      7.60 8.11                                                                         10.64 10.47)                                                                      +57°                                 PhSO.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                                     Oil  2/3 H.sub.2 O                                                                      67.56                                                                             7.27                                                                              6.96                                                                  (67.60                                                                            7.23                                                                              6.85)                                           NH.sub.2 SO.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                              Foam 0.65 CH.sub.2 Cl.sub.2                                                             56.78                                                                             7.16                                                                              10.34                                                                 (56.26                                                                            6.80                                                                              10.75)                                           ##STR41##  Foam  1/2 H.sub.2 O                                                                     62.45 (62.47                                                                      7.48 7.86                                                                         10.74 10.93)                                    Me.sub.2 NSO.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                             Oil 0.1 CH.sub.2 Cl.sub.2                                                               62.03                                                                             7.76                                                                              10.41                                                                 (61.66                                                                            7.91                                                                              11.16)                                          .sup.n BuSO.sub.2 CH.sub.2 CH.sub.2                                                       Oil  1/3 CH.sub.2 Cl.sub.2                                                              62.28                                                                             7.50                                                                              7.23                                                                              +48°                                                       (62.48                                                                            7.91                                                                              7.17)                                           .sup.n PrNHSO.sub.2 CH.sub.2 CH.sub.2                                                     Foam  1/4 H.sub.2 O                                                                     62.07                                                                             7.95                                                                              11.17                                                                             +57°                                                       (62.01                                                                            8.08                                                                              11.42)                                          .sup.n PrSO.sub.2 CH.sub.2 CH.sub.2                                                       Foam  1/20 CH.sub.2 Cl.sub.2                                                            62.80                                                                             7.72                                                                              7.24                                                                              +50°                                             3/4 H.sub.2 O                                                                           (62.47                                                                            8.15                                                                              7.65)                                           .sup.n Pr.sub.2 NSO.sub.2 CH.sub.2 CH.sub.2                                               Gum 1.0 H.sub.2 O                                                                       62.28                                                                             8.38                                                                              10.03                                                                             +40°                                                       (62.37                                                                            8.80                                                                              9.92)                                           EtSO.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                                     Glass 0.5 CH.sub.2 Cl.sub.2                                                             59.10                                                                             7.57                                                                              7.04                                                                  (59.90                                                                            7.47                                                                              7.16)                                            ##STR42##  Foam  1/3 CH.sub.2 Cl.sub.2                                                             59.07 (59.56                                                                      7.10 7.15                                                                         10.80 10.78)                                                                      +30°                                 iPrNHSO.sub.2 CH.sub.2 CH.sub.2                                                           Foam  1/8 CH.sub.2 Cl.sub.2                                                             61.59                                                                             7.88                                                                              11.16                                                                             +68°                                                       (61.39                                                                            7.88                                                                              11.23)                                          __________________________________________________________________________

EXAMPLE 23 General Synthesis of(R)-5-(2-Ethylsulphonylethyl)-3-(pyrrolidin-2-ylmethyl)-1H-indole

A. (R)-3-(N-Benzyloxycarbonylpyrrolidin-2-yl-methyl)-5-bromo-1H-indole

(R)-3-(N-Benzyloxycarbonylpyrrolidin-2-yl-carbonyl)-5-bromo-1H-indole(0.67g, 1.57 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) and atroom temperature under nitrogen was added lithium borohydride (2 molarin tetrahydrofuran) (1.2 mL, 2.4 mmol). The reaction mixture was stirredat room temperature for 3 hours and warmed to reflux for 16 hours. Aftercooling to room temperature, 2NHCl (10 mL) was added dropwise and thereaction mixture partitioned between ethyl acetate and water. Theseparated organic phase was washed with saturated aqueous sodiumhydrogen carbonate (2×), brine (1×), dried (Na₂ SO₄), and evaporated invacuo to give a colourless oil. Purification by column chromatography onsilica gel, eluting with dichloromethane gave the title compound as anoil (0.32 g). TLC (SiO₂ :CH₂ Cl₂): R_(f) =0.2.

B.(R)-5-(Ethylsulphonylethenyl)-3-(N-Benzyloxycarbonylpyrrolidin-2-ylmethyl)-1H-indole

The compound from procedure a) above was coupled with ethylvinylsulphone under standard conditions described above, to give thetitle compound as a foam. Anal. Calcd for C₂₅ H₂₈ N₂ O₄ S•1/8 CH₂ Cl₂ :C, 65.15; H, 6.15; N, 6.05. Found: C,65 16; H,6.17; N,5.97. [α]²⁵ _(D)=-50° (0 1, MeOH).

C. (R)-5-(2-Ethylsulphonylethyl)-3-(pyrrolidin-2-ylmethyl)-1H-indole

The compound prepared in procedure b) above, was hydrogenated under thestandard condition described above, to give the title compound as afoam. Anal. Calcd for C₁₇ H₂₄ N₂ O₂ S•1/2 CH₂ Cl₂ : C,63.07; H,7.48;N,8.63. Found: C,62.90; H,7.25; N,8.58. [α]²⁵ _(D) =-11° (c=0.1, MeOH).

EXAMPLE 24 General Synthesis of(R)-3-(N-alkyl-pyrrolidin-2-ylmethyl)indoles

A.(R)-3-(N-Ethylpyrrolidin-2-ylmethyl)-5-(2-ethylsulphonylethyl)-1H-indole

To a solution of(R)-3-(pyrrolidin-2-ylmethyl)-5-(2-ethylsulphonylethyl)-1H-indole (0.27g, 0.8 mmol) in dimethylformamide (dried over 4A sieves) (5 mls), wasadded sodium carbonate (90 mgs) and ethyl iodide (0.07 mls, 0.88 mmol)at room temperature. The mixture was heated at 120° C. under nitrogenfor 16 hours. After cooling to room temperature the reaction mixture waspartitioned between ethyl acetate and water. The separated organic phasewas washed with water (3×), dried (Na₂ SO₄) and evaporated in vacuo togive an oil. Purification by column chromatography on silica gel,eluting with CH₂ Cl₂ :EtOH:NH₄ OH (90:10:0.5) gave the title compound asa gum (100 mgs). Anal. Calcd for C₁₉ H₂₈ N₂ O₂ S•1/4 CH₂ Cl₂. 1/2 H2O:C,61.04; H,7.85; N,7.40. Found: C,60.80; H,7.69; N,7.48. [α]²⁵ _(D)=+60° (c=0.1, MeOH).

B. The following examples were prepared using the procedure described ina) above but with the appropriate alkyl halide in place of ethyl iodide.The alkyl halide could be iodide or bromide with the optional presenceof sodium iodide. Solvents used were either dimethylformamide ordimethylacetamide.

    __________________________________________________________________________     ##STR43##                                                                                            Analysis %                                                                    (Theoretical in brackets)                                                                 [α].sub.D.sup.25                    R.sup.3      Isolated Form                                                                            C   H   N   c = 0.1 MeOH                              __________________________________________________________________________    iPr          Gum  1/10 CH.sub.2 Cl.sub.2                                                              64.18                                                                             8.17                                                                              7.55                                                                              +24°                                             1/4 H.sub.2 O                                                                           (64.29                                                                            8.24                                                                              7.46)                                          ##STR44##   Gum  1/2 CH.sub.2 Cl.sub.2  1/4 H.sub.2 O                                                60.68 (60.97                                                                      7.91 7.97                                                                         7.08 6.62)                                                                        -3°                                 ##STR45##   Gum  1/8 CH.sub.2 Cl.sub.2                                                               65.19 (65.53                                                                      8.13 8.40                                                                         7.45 7.24)                                                                        +26°                               nPr          Gum  1/20 CH.sub.2 Cl.sub.2                                                              64.04                                                                             8.19                                                                              7.52                                                                              +62°                                             3/5 H.sub.2 O                                                                           (63.77                                                                            8.36                                                                              7.42)                                         (CH.sub.3).sub.2 CHCH.sub.2                                                                Gum  1/2 H.sub.2 O                                                                       65.32                                                                             8.49                                                                              6.87                                                                              +80°                                                       (65.40                                                                            8.63                                                                              7.26)                                          ##STR46##   Gum  2/3 H.sub.2 O                                                                       65.72 (65.63                                                                      8.82 8.85                                                                         7.10 6.96)                                                                        +65°                               __________________________________________________________________________

EXAMPLE 25 (R)-3-(N-Methylpyrrolidin-2-ylmethyl)-1H-indole

(R)-5-Bromo-3-(N-methylpyrrolidin-2-yl-methyl)-1H-indole (60 mg, 0.2mmol) was dissolved in ethanol (1 mL) and hydrogenated over 10%palladium on carbon (45 mg) at 60 p.s.i. of hydrogen pressure at roomtemperature for 16 hours. The reaction mixture was evaporated todryness, and the residue partitioned between ethyl acetate and 10%aqueous sodium carbonate. The organic phase was dried (Na₂ SO₄), andevaporated in vacuo. The resulting residue was purified by columnchromatography on silica gel (eluting with 89:10:1 CH₂ Cl₂ :MeOH:NH₄ OH)to give the title compound (28 mg). Anal. Calcd for C₁₄ H₁₈ N₂ •1/8 CH₂Cl₂ C,75.42; H,8.18; N,12 46 Found: C,75 50; H,8 51; N,12 09. [α]²⁵ _(D)=+60.2° (c=0.088, CHCl₃).

EXAMPLE 26 (R)-3-(N-Benzyloxycarbonylpyrrolidin-2-ylcarbonyl)-5-bromo-1H-indole

Two solutions containing the reactants were prepared separately asfollows: To a stirred solution of N-benzyloxycarbonyl-D-proline (1.0 g)in anhydrous dichloromethane (2 ml) and N,N-dimethylformamide (1 drop)was added oxalyl chloride (0.5 mL), and the resulting solution wasstirred at room temperature for 1.5 hours. The solution was evaporatedunder reduced pressure, and remaining solvent was removed under highvacuum to give the N-benzyloxycarbonyl-D-proline acid chloride. At thesame time, a solution of ethyl magnesium bromide (1.4 mL of a 3Msolution in ether) was added dropwise over 5 minutes to a stirredsolution of 5-bromoindole (0.75 g) in dry ether (18 mL). The mixture wasstirred at room temperature for 10 minutes, heated under reflux for 2hours, then cooled to -30° C. A solution of the aboveN-benzyloxycarbonyl-D-proline acid chloride in dry ether (4 mL) wasadded dropwise with stirring, and stirring was continued for a further 1hour. Ether (12.5 mL) and saturated aqueous sodium bicarbonate (6.5 mL)were added, and the temperature was allowed to rise to room temperature.Stirring was continued for a further 10 minutes and the mixture wasfiltered. The solid was washed well with ethyl acetate, and the combinedfiltrate and washings were washed with water, brine and dried (MgSO₄).Evaporation of the solvent gave an oil which was chromatographed onsilica gel. Elution with ethyl acetate gave the title compound as a foam(0.82 g): LRMS m/z (relative intensity) 428 (M+ with ⁸¹ Br,5) 426 (M+with ⁷⁹ Br, 5), 224 (19), 222 (21), 204 (62), 160 (68), 91 (100). AnalCalcd for C₂₁ H₁₉ BrN₂ O₃ : C, 59.02; H,4.48; N,6.56. Found: C,58.85;H,4.51; N,6.38%.

EXAMPLE 27 (R)-5-Bromo-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole

A solution of(R)-3-(N-benzyloxycarbonyl-pyrrolidin-2-ylcarbonyl)-5-bromo-1H-indole(1.04 g) in dry tetrahydrofuran (20 mL) was added dropwise to a stirredsuspension of lithium aluminium hydride (0.27 g) in dry tetrahydrofuran(15 mL) at room temperature under an atmosphere of dry nitrogen. Themixture was heated under reflux with stirring for 18 hours and thencooled. Additional lithium aluminium hydride (50 mg) was added andrefluxing was continued for an additional 3 hours. The mixture was againcooled, lithium aluminium hydride (40 mg) was added, and refluxing wascontinued for a further 18 hours. The mixture was cooled and water (0.44mL) was carefully added with stirring, followed by 20% aqueous sodiumhydroxide (0.44 mL), followed by more water (1.33 mL). The mixture wasdiluted with ethyl acetate and filtered through Celite (trademark)filter aid. The filtrate was washed with water, brine and then dried(Na₂ SO₄). Evaporation of the solvent gave an oil which waschromatographed on silica gel. Elution withdichloromethane/ethanol/concentrated aqueous ammonia (90:10:0.5) gavethe title compound as a solid (0.51 g), m.p. 137°-140° C. (fromdichloromethane/hexane); IR (KBr) 1620, 1595, 1570, 1480, 1450, 1435cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ11.05 (br s, 1H), 7.65 (br d, 1H), 7.31 (d,J=8.6 Hz, 1H), 7.21 (br d, 1H), 7.16 (dd, J=1.8 and 8.6 Hz, 1H),3.03-2.94 (m, 2H), 2.47 (dd, J=9.2 and 14.0 Hz, 1H), 2.36-2.26 (m, 1H),2.33 (s, 3H), 2.09 (dd, J=8.7 and 17.3 Hz, 1H), 1.73-1.38 (m, 4H); ¹³ CNMR (DMSO-d₆) δ134.8, 129.5, 124.7, 123.2, 120.7, 113.4, 112.1, 110.9,66.1, 57.0, 40.5, 30.9, 29.1, 21.6; LRMS, m/z (relative intensity) 294(M⁺ with ⁸¹ Br, 1), 293 (2), 292 (M⁺ with ⁷⁹ Br, 1), 210 (14), 208 (15),154 (8), 129 (42), 128 (19), 01 (26) 85 (57), 84 (100), 83 (30); [α]²⁵_(D) =+62° (methanol, c=0.10). Anal Calcd for C₁₄ H₁₇ N₂ Br. 0.25H₂ O:C, 56.48; H, 5.93; N, 9.41. Found: C, 56.65; H, 5.69; N,9.23.

EXAMPLE 28(R)-5-(2-Ethylsulphonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole

A mixture of (R)-5-bromo-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole(0.25 g), ethyl vinyl sulphone (0.14 g), tri-o-tolylphosphine (0.075 g),palladium (II) acetate (0.013 g), triethylamine (0.25 mL) andacetonitrile (3 mL) was heated under reflux for 17 hours in anatmosphere of nitrogen. The mixture was evaporated and the residue waschromatographed on silica gel. Elution withdichloromethane/ethanol/concentrated aqueous ammonia (90:8:1) gave thetitle compound as a foam (0. 185 g): TLC(dichloromethane/-ethanol/concentrated aqueous ammonia, 90:10:1): R_(f)=0.5. Anal. Calcd for C₁₈ H₂₄ N₂ O₂ S. 0.2 CH₂ Cl₂ : C,62.55; H,7.04;N,8.02. Found: C,62.65; H,6.94; N,7.92.

EXAMPLE 29(R)-5-(2-Ethylsulphonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)1H-indole

(R)-5-(2-Ethylsulphonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole(157 mg) was dissolved in a mixture of ethanolic hydrogen chloride[prepared by addition of acetyl chloride (0.043 mL) to ethanol (10 mL)],N,N-dimethylformamide (7.5 mL) and water (0.1 mL) and the solution wasshaken under a hydrogen atmosphere (15 psi) at room temperature for 18hours in the presence of 10% palladium on carbon (150 mg). The mixturewas filtered through Arbacel (trade mark) filter aid and the residue waswashed well with ethanol. The combined filtrate and washings wereevaporated under reduced pressure and the residual oil was partitionedbetween ethyl acetate and 2M aqueous sodium carbonate solution. Theorganic layer was separated, washed three times with water followed bybrine and then dried (Na₂ SO₄). Evaporation of the solvent gave an oilwhich was chromatographed on silica gel. Elution withdichloromethane/methanol/concentrated aqueous ammonia (90:10:1) gave thetitle compound as a gum (110 mg): TLC (CH₂ Cl₂ /C₂ H₅ OH/NH₃ ; 90:10:1):Rf=0.3; [α]²⁵ _(D) =+62° (methanol, c=0.10). Anal. Calcd for C₁₈ H₂₆ N₂O₂ S. 0.05 CH₂ Cl₂ : C,63.21; H,7.67; N,8.17. Found: C,63.55; H,7.61;N,8.41.

EXAMPLE 30 (R)-5-(2-Ethylsulphonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indolehemisuccinate

A solution of succinic acid (69 mg) in hot ethanol (3.5 mL) was addedslowly with stirring to a solution of(R)-5-(2-ethylsulphonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indolefree base (390 mg) in ethanol (3.5 mL). The solution was evaporated andthe residue was triturated first with ether and then with ethyl acetateto give the title compound as a solid (375 mg): mp 59°-62° C.: [α]²⁵_(D) =+36° (methanol, c=0.10) Anal Calcd for C₁₈ H₂₆ N₂ O₂ S. 0.5 C₄ H₆O₄. 0.25 CH₃ CO₂ C₂ H₅. 0.5 H₂ O: C,59.00; H,7.42; H,6.68. Found:C,59.17; H,7.37; N,6.73.

EXAMPLE 31(R)-5-(2-Benzenesulphonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indolehydrobromide

A mixture of (R)-5-bromo-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole(0.25 g), phenylvinylsulphone (0.19 g), tri-o-tolylphosphine (0.075 g),palladium (II) acetate (0.0125 g), triethylamine (0.25 mL) andacetonitrile (2.5 mL) was heated under reflux for 42 hours in anatmosphere of nitrogen. The solvent was evaporated and the residue waschromatographed on silica gel. Elution withdichloromethane/methanol/concentrated aqueous ammonia (90:10:1) gave thetitle compound as a foam (0.24 g): Anal. Calcd for C₂₂ H₂₄ N₂ O₂ S. HBr.1/3 CH₂ Cl₂ : C,54,77; H,5,29; N,5.72. Found: C,55.00; H,4.85; N,5.58.

EXAMPLE 32(R)-5-(2-Benzenesulphonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole

A solution of(R)-5-(2-benzenesulphonylethenyl)-3-N-methylpyrrolidin-2-ylmethyl)-1H-indolehydrobromide (0.214 g) and 10% palladium on carbon (0.15 g) in a mixtureof absolute ethanol (10 mL), N,N-dimethylformamide (1 mL) and water (2drops) was shaken under a hydrogen atmosphere (15 psi) at roomtemperature for 18 hours. The mixture was filtered through Celite(trademark) filter aid and the residue was washed well with ethanol. Thecombined filtrate and washings were evaporated under reduced pressureand the residue was partitioned between ethyl acetate and 2M aqueoussodium carbonate solution. The organic layer was separated, washed threetimes with water, followed by brine and dried (Na₂ SO₄). Evaporation ofthe solvent gave a gum which was chromatographed on silica gel. Elutionwith dichloromethane/methanol/concentrated aqueous ammonia (90:10:0.5)gave the title compound as a foam (0.096 g). Anal. Calcd for C₂₂ H₂₆ N₂O₂ S. H₂ O: C,65.97; H,7.05; N,7.00. Found: C,65.51; H,6.77; N,7.45.

EXAMPLE 33(R)-5-(2-Benzenesulphonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indolehemisuccinate

A solution of succinic acid (95 mg) in ethanol (5 mL) was added to asolution of(R)-5-(2-benzenesulphonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indolefree base (620 mg) in ethanol (5 mL). The solution was evaporated togive the title compound as a foam (680 mg): [α]²⁵ _(D) =+29° (methanol,c=0.10). Anal. Calcd for CC₂₂ H₂₆ N₂ O₂ S. 0.5 C₄ H₆ O₄. 0.33 C₂ H₅ OH.0.5 H₂ O; C,63.59; H,6.92; N,6.01. Found: C,63.52; H,6.91; N,6.12.

EXAMPLE 34(R)-5-[2-(4-Methylphenylsulphonyl)ethenyl]-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole

A mixture of (R)-5-bromo-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole(0.40 g), 4-methylphenylvinylsulphone (0.273 g), tri-o-tolylphosphine(0.085 g), palladium (II) acetate (0.031 g), triethylamine (0.42 g), andacetonitrile (20 mL) was heated under reflux for 16 hours in anatmosphere of nitrogen. The mixture was cooled and partitioned betweenethyl acetate and 10% aqueous sodium bicarbonate solution. The organiclayer was washed with brine, dried (Na₂ SO₄) and evaporated. Theresidual orange oil was chromatographed on silica gel. Elution wascommenced with dichloromethane/methanol (90:10), followed bydichloromethane/methanol/concentrated aqueous ammonia (90:10:0.25),gradually increasing the concentration of concentrated aqueous ammoniato 1%. The later product-containing fractions were evaporated to givethe title compound as a foam (226 mg): [α]²⁵ _(D) =+71° (methanol,c=0.10). Anal. Calcd for C₂₃ H₂₆ N₂ O₂ S. 0.15 CH₂ Cl₂ : C,68.27;H,6.51; N,6.88. Found: C,68.26; H,6.54; N,6.99.

EXAMPLE 35(R)-5-[2-(4-Methylphenylsulphonyl)ethyl-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole

A solution of(R)-5-[2-(4-methylphenylsulphonyl)ethenyl]-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole(0.18 g) and 10% palladium on carbon (0.20 g) in ethanolic hydrogenchloride [prepared from absolute ethanol (25 mL) and acetyl chloride (35μL)] was shaken under a hydrogen atmosphere (15 psi) at room temperaturefor 16 hours. The reaction mixture was filtered through Celite(trademark) filter aid and the residue was washed well with ethanol. Thecombined filtrate and washings were evaporated under reduced pressureand the residue was partitioned between ethyl acetate and 2M aqueoussodium carbonate solution. The organic layer was saturated, washed threetimes with water, followed by brine and dried (Na₂ SO₄). Evaporation ofthe solvent gave a gum which was chromatographed on silica gel. Elutionwith dichloromethane/methanol/concentrated aqueous ammonia (90:10:0.25)gave the title compound as a foam (108 mg): [α]²⁵ _(D) =+30° (methanol,c=0.10) Anal. Calcd. for C₂₃ H₂₈ N₂ O₂ S. 0.05 CH₂ Cl₂. 0.5 H₂ O:C,67.55; H,7.15; N,6.84. Found: C,67.51; H,7.04; N,6.98.

EXAMPLE 36 4-(Nitrophenyl)methanesulphonyl chloride

To a stirred solution of sodium thiosulphate (72.0 g, 0.291 mol) inwater (75 mL) and methanol (50 mL) was added at room temperature, over 5minutes, 4-nitrobenzyl chloride (50.0g, 0.291 mol). The resultingreaction mixture was heated to reflux and stirred, at reflux, for afurther 2.25 hours. The reaction mixture was then cooled down andevaporated under reduced pressure, azeotroping with toluene to give awhite solid (150 g). The white solid was added to a mixture of aceticacid (75 mL), water (100 mL) and ice, the reaction mixture cooled to 0°C. and chlorine gas passed through the system for 1.25 hours,maintaining the reaction temperature below 10° C. throughout. The excesschlorine gas was removed by purging the reaction mixture with nitrogengas for 1.25 hours. The resulting slurry was filtered, drying the solidthus obtained in air. The title compound thus obtained (60.5 g) was usedas such in Example 37 without further purification or characterization.

EXAMPLE 37 4-t-Butylaminosulphonylmethylnitrobenzene

To a cooled (ice bath) solution of t-butylamine (48.45 mL, 461 mmol) indichloromethane (500 ml) was added dropwise, with stirring, a solutionof the product of Example 36 (54.33 g, 231 mmol) in dichloromethane (500mL). This addition was carried out over 15 minutes with the temperaturemaintained below 10° C. throughout. The reaction was then allowed towarm to room temperature and stirred for a further 12 hours. Thereaction was then diluted with water (200 mL), the organic layerseparated, washed sequentially with water and brine, dried (MgSO₄) andevaporated under reduced pressure to give the product as a brown solid.Recrystalization of the brown solid from ethanol gave the title compoundas a white solid (49.0 g): mp, 156-158° C.; TLC(dichloromethane/methanol 30:0.4): Rf=0.66. ¹ H NMR(CDCl₃) δ8.25 (d,2H), 7.6 (d, 2H), 4.40 (s, 2H), 4.10 (s, 1H), 1.38 (s, 9H). Anal. calcd.for C₁₁ H₁₆ N₂ O₄ S: C, 48.55; H, 5.97; N, 10.30. Found: C, 48.53; H,5.92; N, 10.29.

EXAMPLE 38 4-t-Butylaminosulphonylmethylaniline

A solution of the product of Example 37 (1.17 g, 4.29 mmol) in absoluteethanol and 10% palladium on carbon (0.32 g) was stirred under ahydrogen atmosphere (60 psi) at 60° C. for 66 hours. The mixture wasfiltered through CELITE filter aid and the resulting solution evaporatedunder reduced pressure to give the product as a solid. Recrystallizationfrom ethanol gave the title compound as a white solid (0.95 g): mp,137°-138° C.; TLC (dichloromethane/methanol 30:0.4): Rf=0.43. ¹ H NMR(CDCl₃) δ7.20 (d, 2H), 6.65 (d, 2H), 4.15 (s, 2H), 3.95 (br s, 1H), 3.75(br s, 2H), 1.32 (s, 9H). Anal. calcd. for C₁₁ H₁₈ N₂ O₂ S: C, 54.51; H,7.49; N, 11.56. Found: C, 54.76; H, 7.60; N, 11.43.

EXAMPLE 39 4-(t-Butylaminosulphonylmethyl)-2,6-dibromoaniline

To a stirred solution of the product of Example 38 (0.77 g, 3.17 mmol)in dichloromethane (15 mL) and methanol (15 mL) was added sodiumbicarbonate (0.80 g, 9.53 mmol) with stirring, at 20° C. Bromine (0.315mL, 6.11 mmol) was then added dropwise, to the resultant slurry. Theresulting mixture was then stirred for 18 hours concentrated in vacuoand taken up in ethyl acetate/water (1:1). The aqueous layer wasseparated and extracted with ethyl acetate. The combined organic layerswere then washed with water, dried (MgSO₄) and evaporated under reducedpressure to give the product as a white solid. Recrystalization fromhexane/ethyl acetate gave the title compound as a white solid (1.15 g).Mp 140°-142° C.; TLC (dichloromethane/methanol 30:0.4): Rf=0.60. ¹ H NMR(CDCl₃) δ7.45 (s, 2H), 4.65 (br s, 2H), 4.05 (s, 2H), 4.00 (s, 1H), 1.40(s, 9H). Anal. calcd. for C₁₁ H₁₆ N₂ O₂ SBr₂ : C, 33.02; H, 4.03; N,7.00. Found: C, 33.52; H, 4.04; N, 6.92.

EXAMPLE 404-t-Butylaminosulphonylmethyl-2,6-dibromo-N-trifluoroacetylaniline

To a stirred solution of the product of Example 39 (1.01 g, 2.52 mmol)and pyridine (0.26 mL, 3.28 mmol, 1.30 eq) in anhydrous methylenechloride (15 mL) at 0° C. under a nitrogen atmosphere was added dropwisetrifluoroacetic anhydride (0.38 ml, 2.68 mmol, 1.1 eq). The resultantreaction mixture was stirred at 0° C., under a nitrogen atmosphere, for1 hour. The reaction mixture was then diluted with dichloromethane (150mL), washed with water (2×50 mL) and dried (MgSO₄). Evaporation underreduced pressure gave a white solid which was recrystallized fromhexane/diethyl ether to give the title compound as a white solid (1.10g) mp 166°-167° C.; TLC (dichloromethane/methanol 30:0.4): Rf=0.21. ¹ HNMR (CDCl₃) δ7.75 (br s, 1H), 7.70 (s, 2H), 4.20 (s, 2H), 4.10 (s, 1H),1.45 (S, 9H). Anal calcd. for C₁₃ H₁₅ N₂ O₃ SBr₂ F₃ : C, 31.48; H, 3.05;N, 5.65. Found: C, 31.41; H, 3.11, N, 5.55.

EXAMPLE 41(R)-1-(N-Benzyloxycarbonylpyrrolidin-2-yl)-3-[N-(4-t-butylaminosulphonylmethyl-2,6-dibromophenyl)-N-trifluoroacetylamino]propene

To a stirred solution of the product of Example 40 (28.0 g, 56.0 mmol)and triphenylphosphine (15.0 g, 86.0 mmol, 1.53 eq) in anhydroustetrahydrofuran (70 mL), under a nitrogen atmosphere, at 10° C., wasadded dropwise a solution of diethylazodicarboxylate (8.9 mL, 56 mmol)in anhydrous tetrahydrofuran (15 mL). The reaction solution was thenwarmed to 25° C. and stirred for a further 25 minutes whereupon asolution of the product of Example 12A (14.79 g, 57.0 mmol) in anhydroustetrahydrofuran (45 mL) was added dropwise, over 10 minutes. Thereaction solution was then stirred at 25° C., under a nitrogenatmosphere for 18 hours. The resulting reaction solution was evaporatedunder reduced pressure, triturated with diethyl ether, filtered and thefiltrate evaporated under reduced pressure and the residue was columnchromatographed using silica gel (approximately 850 g), eluting with anethyl acetate gradient in hexanes to afford the title compound as awhite foam. TLC (hexane/ethyl acetate 1:1): Rf=0.65. ¹ H NMR (CDCl₃)[Note: due to slow nitrogen inversion two conformers of the products areseen by NMR spectroscopy] δ7.50-7.80 (m, 2H), 7.25-7.42 (m, 5H),5.42-5.65 (m, 2H), 5.30 (s, 0.14H), 5.00-5.20 (m, 2H), 4.02-4.55 (m,6H), 3.28-3.45 (m, 2H), 1.25-1.90 (m, 13H). Anal calcd for C₂₈ H₃₂ N₃ O₅SBr₂ F₃. 7/100 CH₂ Cl₂ : C, 45.23; H, 4.34; N, 5.64. Found: C, 45.06; H,4.44; N, 5.87.

EXAMPLE 42(R)-3-(N-Benzyloxycarbonylpyrrolidin-2-ylmethyl)-7-bromo-5-(t-butylaminosulphonylmethyl)-1H-indole

To a stirred solution of the product of Example 41 (29.90 g, 40.44 mmol)in 1,2-dimethoxyethane (160 mL) under a nitrogen atmosphere, at 20° C.was added palladium (II) acetate (0.97 g, 4.32 mmol) followed bytetrabutylammonium chloride hydrate (11.25 g, 40.48 mmol) andtriethylamine (22.3 mL, 160 mmol). The reaction solution was stirred fora further hour at 20° C. and then heated at reflux for 18 hours. Thereaction solution was then allowed to cool to 20° C., evaporated underreduced pressure, taken up in ethyl acetate (800 mL) and washed withwater. The organic layer was separated, dried (MgSO₄) and evaporatedunder reduced pressure to give a dark brown foam. Column chromatographyusing elution with 10% acetone in dichloromethane failed to provide amore pure title compound. The resulting crude product (21.3 g of anoff-white foam) was used as such in the preparation of Example 43.

EXAMPLE 43(R)-7-Bromo-5-(t-butylaminosulponylmethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole

To a stirred suspension of lithium aluminium hydride (7.07 g, 186 mmol)in anhydrous tetrahydrofuran (100 mL), at 0° C., under a nitrogenatmosphere, was added dropwise, over 30 minutes, a solution of theresulting product of Example 42 (21.3 g) in anhydrous tetrahydrofuran(100 mL). The resulting mixture was allowed to warm to room temperatureand then stirred for a further 56 hours. The reaction was then cooled to0° C. and cautiously treated with water (7.0 mL), followed by 15%aqueous sodium hydroxide solution (7.0 mL), and then with more water(21.0 mL). The resulting black precipitate was removed by filtration,washing with ethyl acetate. The filtrate was then washed with water,dried (MgSO₄) and evaporated under reduced pressure to give the crudeproducts as a gum. This was column chromatographed using silica gel (50g) and elution with dichloromethane/methanol (100:5) followed bydichloromethane/methanol/ammonium hydroxide (90:10:1) to afford thetitle compound (9.9g) as a white foam. TLC(dichloromethane/methanol/ammonium hydroxide 90:10:1): Rf=0.33. ¹ H NMR(CDCl₃) δ8.35 (br s, 1H), 7.52 (s, 1H), 7.40 (s, 1H), 7.12 (s, 1H), 4.30(s, 2H), 4.00 (s, 1H), 3.12-3.25 (m, 2H), 2.60-2.72 (m, 1H), 2.50-2.10(m, 1H), 2.49 (s, 3H), 2.22-2.38 (m, 1H), 1.55-1.78 (m, 4H), 1 39 (s,9H) [α]²⁵ _(D) =+47° (CH₃ OH, c=0.1) Anal. calcd. for C_(19l) H₂₈ N₃ O₂SBr: C, 51.59; H, 6.38; N, 9.50. Found: C, 51.84; H,6.52; N, 9.52.

EXAMPLE 44(R)-5-(t-Butylaminosulphonylmethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole

A solution of the product of Example 43 (5.79 g, 13.1 mmol) and 20%palladium hydroxide/carbon (5.7 g) was stirred under a hydrogenatmosphere (60 psi) for 24 hours. The resultant reaction mixture wasfiltered through a pad of CELITE, washing with absolute ethanol. Thecombined filtrates were evaporated under reduced pressure. The residuewas taken up in a mixture of 2N sodium bicarbonate and dichloromethane.The organic layer was separated, dried (MgSO₄) and evaporated underreduced pressure. This was column chromatographed using silica gel (90g) and elution with dichloromethane/methanol/ammonium hydroxide(90:10:1) to afford the title compound as a white solid (3.0 g). mp73°-75° C. TLC (dichloromethane/methanol/ammonium hydroxide 90:10:1):Rf=0.36. ¹ H NMR (CDCl₃) δ8.25 (br s, 1H), 7.60 (s, 1H). 7.35 (d, 1H),7.22 (d, 1H), 7.05 (s, 1H), 5.25 (s, 1/5H), 4.35 (s, 2H), 3.90 (s, 1H),3.10-3.22 (m, 2H), 2.55-2.70 (m, 1H), 2.42-2.55 (m, 1H), 2.45 (s, 3H),2.18-2.30 (m, 1H), 1.50-1.90 (m, 4H), 1.40 (s, 9H). [α]2s =58° (CH₃ OH,c=0.1). Anal calcd for C₁₉ H₂₉ N₃ O₂ S•1/10 CH₂ Cl₂ : C, 61.68; H, 7.91;N, 11.29. Found : C, 61.67; H, 8.14; N, 11.30.

EXAMPLE 45(R)-5-(Aminosulphonylmethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole

A solution of the product of Example 44 (5.92 g, 16.3 mmol) andp-toluenesulphonic acid (470 mg, 2.5 mmol) in acetic anhydride (90 mL)was refluxed, under a nitrogen atmosphere, for 6 hours. The reactionmixture was then cooled to 25° C. and evaporated under reduced pressure,azeotroping with toluene and dichloromethane. The resultant dark brownfoam was dissolved in trifluoroacetic acid (50.0 mL) and stirred under anitrogen atmosphere at 25° C. for 18 hours. The reaction mixture wasthen evaporated under reduced pressure, azeotroping withdichloromethane. A slurry of potassium carbonate (1.86 g) in methanol(85 mL) was added to the resultant gum and the reaction mixture heatedto reflux for 30 minutes. The resultant reaction mixture was then cooledto 25° C. and evaporated under reduced pressure to give a black oil.Purification by column chromatography using silica gel and elution withmethylene chloride/methanol/ammonium hydroxide (90:10:1) afford thetitle compound as a white foam (2.6 g). TLC(dichloromethane/methanol/ammoniumhydroxide 80:20:1): Rf=0.43. ¹ H NMR(CD₃ OD) δ7.62 (s, 1H), 7.35 (d, 1H), 7.18 (d, 1H), 7.10 (s, 1H), 5.48(s, 9/10H), 4.40 (s, 2H), 3.08-3.30 (m, 2H), 2.55-2.70 (m, 2H), 2.50 (s,3H), 2.20-2.42 m, 1H), 1.52-1.90 (m, 4H). [α]²⁵ _(D) =65° (CH₃ OH,c=0.1). Anal. calcd. for C₁₅ H₂₁ N₃ SO₂ •9/20 CH₂ Cl₂ : C, 53.69; H,6.39; N, 12.16. Found: C, 53.58; H, 6.45; N, 11.76.

EXAMPLE 46 4-Methylaminosulfonylmethyl-N-trifluoroacetylaniline

To a chilled solution of pyridine (4 mL) in methylene chloride (100 mL)was added trifluoroacetic anhydride (7.0 m L) follow e d by4-methylaminosulfonylmethylaniline (9.55 g). After 30 minutes at 0° C.,the reaction mixture was filtered to give the title compound (11.6 g) asa light yellow powder. TLC (EtOAc/hexane 2:1) Rf=0.36.

EXAMPLE 47 2-Bromo-4-methylaminosulfonylmethyl-N-trifluoroacetylaniline

To a chilled suspension of4-methylaminosulfonylmethyl-N-trifluoroacetylaniline(10.9 g) in methanol(100 mL) was added sodium bicarbonate (28 g), followed by bromine (18.3g) in methylene chloride (30 mL). The reaction mixture was then dilutedwith methylene chloride (70 mL) and quenched by the addition of sodiumsulfite (20 g), filtered through CELITE and concentrated in vacuo to ayellow residual solid. This solid was twice reslurried in methylenechloride (300 mL) then refiltered and the filtrates evaporated in vacuo.The residual materials were combined in 10% acetone/methylene chloridesolution and concentrated then purified by column chromatography(eluting with 4% acetone in methylene chloride) to give the titlecompound (4.10g) mp 170° C.; TLC (methylene chloride/acetone 15:1)Rf=0.36, and the corresponding dibromide (5.56 g) TLC (methylenechloride/acetone 15:1) Rf=0.31.

EXAMPLE 48 2,6-Dibromo-4-methylaminosulfonylmethylaniline

To a stirred solution of 4-methylaminosulfonylmethylaniline (10 g) in amixture of methylene chloride (100 mL) and methanol (200 mL) was addedsodium bicarbonate (12.6 g) followed by bromine (16 g) in methylenechloride (80 mL). Then the reaction mixture was evaporated in vacuo andthe residue partitioned between ethyl acetate (200 mL) and water (100mL). The ethyl acetate phase was washed with water and brine then driedand evaporated to give the title compound as a brown solid (17.1 g). mp155°-157° C. ¹ H NMR (CDCl₃) δ7.4 (s, 2H), 4.6 (bs, 2H), 4.1 (m, 3H),2.75 (d, 3H).

EXAMPLE 492,6-Dibromo-4-methylaminosulfonylmethyl-N-trifluoroacetylaniline

2,6-Dibromo-4-methylaminosulfonylmethylaniline (410 g) was stirred inmethylene chloride (8 L) containing pyridine (118 g) and treated withtrifluoroacetic anhydride (307.5 g) in methylene chloride (300 mL). Uponcomplete consumption of the aniline the reaction mixture was dilutedwith methylene chloride (2 L) and with water (5 L) resulting inprecipitation of the title compound (281.9 g) which was removed byfiltration. mp 179°-180° C. TLC (EtOAc/hexane 1:1): Rf=0.3. Anal calcd.for C₁₀ H₉ Br₂ F₃ N₂ O₃ S: C, 26.45; H, 2.00; N, 6.17. Found C 26.46; H,1.79; N, 6.12.

Further title compound (165 g) was recovered by crystalization from the(water-washed) combined filtrate and washes upon concentration.

EXAMPLE 50 (R)-1-(N-Benzyloxycarbonylpyrrolidin-2-yl)-3-hydoxypropene

To a stirred solution of (R)-ethyl3-(N-benzyloxycarbonylpyrrolidin-2-yl)-2-propenoate (574 g) intetrahydrofuran (5.7 L) at about -78° C. was added boron trifluorideetherate (295.4 g) and then diisobutylaluminum hydride (1.5M in toluene,3.91 L, 3.1 eq) added (over two hours) maintaining the temperature below-62° C. The resulting solution was stirred (between -78° and -62° C.)for three hours and then quenched into aqueous citric acid solution (2kg citric acid in 5 L water plus 4 L ice) over about 40 minutes. Thephases were separated and the aqueous phase extracted with ethyl acetate(2×2.1 L). The combined organic solution was dried (over magnesiumsulphate) and evaporated, then the residual oil purified bychromatography through silica gel, eluting with mixed ethylacetate/hexane (9:1 to 4:1) to give the-title compound as an oil (260g), as produced in Example 12A (as an alternative, the residual oil canbe purified by chromatography through silica gel eluting with ethylacetate:hexane (1:1)).

EXAMPLE 51(R)-1-(N-Benzyloxycarbonylpyrrolidin-2-yl)-3-IN-(4-methylaminosulfonylmethyl-2,6-dibromophenyl)-N-trifluoroacetylamino]propene

Triphenylphosphine (5.71 g) was dissolved in anhydrous tetrahydrofuran(30 mL) and, in an ice bath, diethylazodicarboxylate (3.71 g in 20 mLanhydrous THF) was added dropwise. Having removed the ice-bath, thereaction mixture was diluted with a further 20 mL anhydrous THF,followed by2,6-dibromo-4-methylaminosulfonylmethyl-trifluoroacetylaniline (6.45 gin 50 mL anhydrous THF), and(R)-1-(N-Benzyloxycarbonylpyrrolidin-2-yl)-3-hydroxypropene (5.51 g in30 mL anhydrous THF) added dropwise. When conversion was judged completethe reaction mixture was evaporated in vacuo (onto silica gel -20 g) andpurified by column chromatography (SiO2-1.6 kg) eluted with 5% acetonein methylene chloride to give the title compound as a colorless foam(9.13 g). TLC (methylene chloride/acetone 9:1) Rf=0.60; Anal Calcd. forC₂₅ H₂₆ Br₂ F₃ N₃ O₅ S C 43.1; H, 3.7; N, 6.0. Found C, 43,93; H, 3.99;N, 6.00.

Similarly, the reaction may be conducted in 1,2-dimethoxyethane solventand processed without purification to directly yield the compound ofExample 52 under standard Heck coupling conditions (in mixed1,2-dimethoxyethane with N,N-dimethylformamide).

EXAMPLE 52(R)-3-(N-Benzyloxycarbonylpyrrolidin-2-ylmethyl)-7-bromo-5-(methylaminosulfonylmethyl)-1H-indole

(R)-1-(N-Benzyloxycarbonylpyrrolidin-2-yl)-3-[N-(4-methylaminosulfonylmethyl-2,6-dibromophenyl)-N-trifluoroacetylamino]propene(9.00 g) in triethylamine (70 mL) containing N,N-dimethylformamide (20mL), tetra-n-butylammonium chloride (3.61 g) and palladium acetate (1.01g) was heated at 80° C. until conversion was complete. The cooledreaction mixture was filtered through CELITE and washed with methylenechloride. The combined filtrate and washings were then evaporated invacuo onto silica gel (15 g) then purified by column chromatography(SiO2-1.6 kg) eluted with 4% acetone in chloroform. The product-richfractions were combined and evaporated then re-purified bycrystallisation from a mixture of diethyl ether (50 mL) and methylenechloride (10 mL). The title compound was recovered by filtration(washing with hexanes) as a colorless solid (2.40 g). TLC (methylenechloride/acetone 10:1) Rf=0.35; Anal calcd. for C₂₃ H₂₆ BrN₃ O₄ S: C,53.1; H, 5.0; N, 8.1. Found C, 53.13; H, 5.0; N, 7.8.

Further title compound (2.03 g) was recovered from the crystallisationliquor upon evaporation and purification by silica chromatography (300 gSiO2 eluted with diethyl ether).

EXAMPLE 53(R)-7-Bromo-5-(methylaminosulfonylmethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole

To a chilled suspension of lithium aluminium hydride (47.89 g) intetrahydrofuran (938 mL),(R)-3-(N-benzyloxycarbonylpyrrolidin-2-ylmethyl)-7-bromo-5-(methylaminosulfonylmethyl)-1H-indole(262.7 g) in tetrahydrofuran (1250 mL total) was added slowly dropwise.The reaction mixture was stirred at ambient temperature and then warmedto 40° C. until conversion was complete. Then, the mixture was cooledand quenched by slow addition of industrial methylated spirit (160 mL),followed by 4M aqueous sodium hydroxide solution (45 mL), then water(142 mL). The mixture was then filtered (through Arbacel). The filteredsolids were reslurried in hot industrial methylated spirit (1600 mL)then refiltered. The filtered solids were then washed with a furtherportion of industrial methylated spirit (200 mL) and then againreslurried from hot industrial methylated spirit (1600 mL). Theresultant slurry was again refiltered. The combined filtrates andwashings were evaporated in vacuo to give a crude oil which was stirredin mixed water (1000 mL)/ethyl acetate (1000 mL). The aqueous phase wasseparated and washed with ethyl acetate (500 mL) (then the aqueousdiscarded) and then the ethyl acetate extracts combined and diluted withwater (1000 mL) and the whole acidified (by addition of concentratedhydrochloric acid). The aqueous phase was separated and the organicphase washed with water (500 mL). These two aqueous phases were combinedand made basic (by addition of 40% aqueous sodium hydroxide solution)and the product re-extracted with ethyl acetate (2×1000 mL), then againat pH9 with further ethyl acetate (500 mL). The combined ethyl acetateextracts were evaporated to an oil then reevaporated from acetone (250mL) to give the title compound (200.7 g) as a semi-solid mass. TLC(diethyl ether/ethyl acetate/methanol/diethyl amine 50:50:5:5): Rf=0.26.¹ H NMR (d₆ DMSO) δ11.05 (s, 1H), 7.5 (s, 1H), 7.3 (s, 1H), 7.2 (s, 1H),6.85 (q, 1H), 4.35 (s, 2H), 2.95 (m, 2H), 2.55 (d, 3H), 2.5 (m, 1H),2.35-2.3 (m, 1H and s, 3H), 2.1 (m, 1H), 1.75-1.4 (m, 4H).

EXAMPLE 54(R)-5-(Methylaminosulfonylmethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole

A solution of(R)-7-bromo-5-(methylaminosulfonylmethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole(193 g) in industrial methylated spirit (950 mL) containing Pearlman'scatalyst (47.6 g total) was exposed to hydrogen gas (50 psi). Thecatalyst was then filtered through an Arbacel pad, washing with hotindustrial methylated spirit (2×100 mL) and the combined filtrate andwashings evaporated in vacuo to an organic residue. The filtered solids(catalyst +filter aid) were then reslurried in 2N hydrochloric acid (500mL) then refiltered (through Arbacel)and the filtrand washed with 2Nhydrochloric acid (4×250 mL) and water (2×100 mL). The aqueous filtrateand washes were combined with the organic residue and then once washedwith ethyl acetate (1000 mL). The aqueous solution was chilled then madebasic by addition of 40% aqueous sodium hydroxide solution precipitatingthe title compound as a pale-yellow solid. This solid was filtered,washed with water (2×100 mL) and dried in vacuo to give the titlecompound (89.9 g). TLC (methyl iso-butyl ketone/acetic acid/water 2:1:1Top phase): Rf=0.23. ¹ H NMR(d₆ DMSO) δ10.85 (s, 1H), 7.5 (s, 1H), 7.3(d, 1H), 7.15 (s, 1H), 7.05 (d, 1H), 6.8 (q, 1H), 4.35 (s, 2H), 3.0 (m,2H), 2.55-2.4 (d, 3H and m, 2H), 2.35 (s, 3H), 2.1 (m, 1H), 1.7-1.4 (m,4H).

Further title compound (32.4 g) could be recovered from the catalystsolids by repeating the extractions into 2N hydrochloric acid and waterand again precipitating solid product by the addition of aqueous sodiumhydroxide solution.

EXAMPLE 55(R)-5-(Methylaminosulfonylmethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole

(R)-3-(N-Benzyloxycarbonylpyrrolidin-2-ylmethyl)-7-bromo-5-(methylaminosulfonylmethyl)-1H-indole(3.0 g) in ethanol (45 ml) was exposed to hydrogen (15 psi) overPearlman's catalyst (1.5 g) until complete consumption of the substratewas evident (if necessary a second charge of catalyst can be made afterfiltration of the original catalyst through Arbacel and washing thefiltered solids with ethanol -50 ml). Then the reaction was filteredthrough Arbacel (washing with ethanol -150 ml) and the combined filtrateand washings evaporated (and reevaporated from methylene chloride) to anoff-white solid (the hydrobromide salt of(R)-5-(methylaminosulfonylmethyl)-3-(pyrrolidin-2-ylmethyl)-1H-indole)which was dissolved in water (100 ml). From this aqueous solution(R)-5-(methylaminosulfonylmethyl)-3-(pyrrolidin-2-ylmethyl)-1H-indole(1.4 g) was extracted into ethyl acetate (ca. 850 ml) after addition of15% aqueous sodium hydroxide solution to pH 8.

(R)-5-(Methylaminosulfonylmethyl)-3-(pyrrolidin-2-ylmethyl)-1H-indole(1.3 g) in tetrahydrofuran (12 mL) was treated with an aqueous solution(12 mL) of the mono-sodium salt of phosphorous acid (made from 169 mgsodium hydroxide and 346 mg phosphorous acid). To this mixture was added37% aqueous formaldehyde (343 mg) and then the reaction mixture washeated to 60° C. until conversion was complete. The organic solvent wasremoved by atmospheric distillation then made basic by addition ofaqueous sodium hydroxide solution (to pH 10). This causes precipitationof the title compound (0.945 g).

Similarly, the hydrobromide salt of(R)-5-(methylaminosulfonylmethyl)-3-(pyrrolidin-2-ylmethyl)-1H-indolemay be used directly in the reductive amination process (above) simplyby incorporation of an extra molar equivalent of sodium hydroxide in theaqueous solution.

EXAMPLE 56(R)-3-(N-Benzyloxycarbonylpyrrolidin-2-ylcarbonyl)-5-bromo-1H-indole

Two solutions containing the reactants were prepared separately asfollows:

To a stirred solution of N-benzyloxycarbonyl-D-proline (291.93 g) indichloromethane (291.9 mL) and toluene (370.8 mL) containingN,N-dimethylformamide (1.46 mL) was added oxalyl chloride (102.2 mL) intoluene (291.9 mL) and the resulting solution was stirred at ambienttemperature overnight. The solution was then purged by passing a streamof dry nitrogen gas for five hours. This solution ofN-benzyloxycarbonyl-D-proline acid chloride was ready for use.

In parallel, a solution of ethyl magnesium bromide (800 mL of a 3Msolution in ether) was added dropwise over one hour to a stirredsolution of 5-bromoindole (459.15 g) in dichloromethane (4391.4 mL). Themixture was stirred and heated at reflux for 30 minutes then cooled to-20° C. The above solution of N-benzyloxycarbonyl-D-proline acidchloride was added dropwise with stirring (over one hour) and stirringwas continued for a further 30 minutes. Then a solution of ammoniumchloride (1122.3 g) in water (5855.3 mL) was added at this temperatureand the mixture allowed to warm to room temperature. Further ammoniumchloride (1452.3 g) in water (2000 mL) was added to allow separation ofthe phases. The phases were separated and the aqueous phase extractedwith dichloromethane (1.95 L) then discarded. The combined organicphases were washed with aqueous sodium bicarbonate solution (2.7 L),then with brine (1 L) before concentration to low volume (about 1 L).This concentrate was diluted with ethyl acetate (1250 mL) and thenfurther diluted with hexane (1250 mL). The resulting slurry was stirredat ambient temperature before collection of the title compound (361.4 g)by filtration (washing with 1:1 ethyl acetate:hexane-2×300 ml) anddrying in vacuo. This material is as described in Example 26.

EXAMPLE 57(R)-1-Acetyl-5-(2-phenylsulfonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole

A solution of (R)-5-bromo-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole(50 g) in dimethylformamide (40 mL) containing triethylamine (18.98 g)was treated with acetic anhydride (19.15 g) over ten minutes, then themixture was heated to 90°-100° C. for two hours then allowed to cool.This solution was added (over ten minutes, washing in with 20 mL of DMF)to a solution of palladium acetate (1.91 g), tri-o-tolylphosphine (5.20g), phenyl vinyl sulphone (35.86 g) and triethylamine (36.24 g) indimethylformamide (90 mL) and the mixture was heated to reflux for threehours. The mixture was then cooled and filtered through Arbacel (washingwith dimethylformamide-2×50 mL-then with water-2×50 mL). This solution(in two portions) was quenched into dilute aqueous hydrochloric acid(3016 mL total) then the pH of the aqueous solutions adjusted to about 8(by addition of aqueous sodium hydroxide). The precipitated materialswere filtered, washed with water (each twice with 50 mL) then dried invacuo (to 78.65 g). This material (74.57 g) was reslurried in methanol(500 mL) containing water (250 mL) then refiltered, washing with 2:1methanol:water mixture (2×50 mL) then dried in vacuo to give the titlecompound as a beige solid (57.55 g): mp, 86°-90° C.; IR (KBr) 1700,1605, 1460, 1450, 1385, 1150, 1085, cm⁻¹ ; LRMS (TSP), m/z 423, 381,165, 135, 133.

EXAMPLE 58(R)-5-(2-Phenylsulfonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole

A suspension of(R)-1-acetyl-5-(benzenesulfonylethenyl)-3-(N-methyl-pyrrolidin-2-ylmethyl)-1H-indole(220.8 g) in methanol (2.21 L) was treated with potassium carbonate(72.23 g) and stirred at ambient temperature. After about one houractive carbon (22.1 g) was added to the solution then water (660 mL)added slowly. The mixture was filtered and the filtrate heated to refluxand water (660 mL) added dropwise. The mixture was allowed to cool andcrystallize, then further water was added slowly (3.31.1). The resultingsolid was filtered, washed with 1:2 methanol:water mixture (2×200 mL)then dried in vacuo to give the title compound (149 g): mp, 84°-87° C.IR (KBr) 1600, 1450, 1290, 1145, 1085 cm⁻¹ : ¹ H NMR (CDCl₃) 8.4 (b,1H), 8.0 (d, 2H), 7.8 (d, 1H), 7.7 (s, 1H), 7.6-7.5 (m, 3H), 7.3 (s,2H), 7.05 (b, 1H), 6.75 (d, 1H), 3.15 (re, 2H), 2.6 (111, 1H), 2.45 (s,3H), 2.4 (s, 1H), 2.2 (111, 1H), 2.0-0.5 (m, 4H); LRMS (TSP), ml/z 381,165, 133,119.

EXAMPLE 59(R)-5-(2-Phenylsulfonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole

A stirred solution of(R)-5-(2-benzenesulfonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole(34.0 g) in acetone (200 mL) was treated with methanesulfonic acid (8.5871 g) then 5% palladium on carbon (50% wet) (34.0 g) added and themixture exposed to hydrogen (50 psi) at ambient temperature. Whenconversion was judged to be complete the mixture was filtered (washingwith acetone--85 mL--and mixed acetone/water--81 mL/4 mL). The combinedfiltrate and washings were diluted with water (800 mL) and the pHadjusted (with stirring) to about 11 by addition of 40% aqueous sodiumhydroxide. After granulation of the precipitate the solids werecollected by filtration to give the title compound (25.08 g) as thatproduced in Example 32).

We claim:
 1. A compound of the formula ##STR47## wherein n is 0, 1, or2; X is hydrogen, chlorine, bromine, or iodine; R₁ is hydrogen; R₂ isselected from hydrogen, halogen, cyano, --OR₄, --(CH₂)_(m) --(C═O)NR₅R₆, [--(CH₂)_(m) --SO₂ NR₄ R₅,]--(CH₂)_(m) --NR₇ (C═O)R₈, --(CH₂)_(m)--NR₇ SO₂ R₈, --(CH₂)_(m) --S(O)_(x) R₈, --(CH₂)_(m) --NR₇ (C═O)NR₅ R₆,--(CH₂)_(m) --NR₇ (C═O)OR₉, and --CH═CH(CH₂)_(y) R₁₀ ; R₃ is hydrogen,C₁ to C₆ linear or branched alkyl; R₄ is selected from hydrogen, C₁ toC₆ alkyl, and aryl; R₅ and R₆ are independently selected from hydrogen,C₁ to C₆ alkyl, aryl, and C₁, to C₃ alkyl-aryl or R₅ and R₆ takentogether to form a 4, 5, or 6 membered ring; R₇ and R₈ are independentlyselected from hydrogen, C₁ to C₆ alkyl, aryl, and C₁ to C₃ alkyl-aryl;R₉ is selected from hydrogen, C₁ to C₆ alkyl, aryl, and C₁ to C₃alkyl-aryl; R₁₀ is selected from --(C═O)NR₅ R₆ and --SO₂ NR₅ R₆, whereinR₅ and R₆ are defined as above, and --NR₇ (C═O)R₈, --NR₇ SO₂ R₈, --NR₇(C═O)NR₅ R₆, --S(O)_(x) R₈ and --NR₇ (C═O)OR₉, wherein R₇, R₈, and R₉are as defined above; y is 0, 1, or 2; x is 1 or 2; m is 0, 1, 2, or 3;and the above aryl groups and the aryl moieties of the above alkylarylgroups are independently selected from phenyl and substituted phenyl,wherein-said substituted phenyl may be substituted with one to threegroups selected from C₁ to C₄ alkyl, halogen, hydroxy, cyano,carboxamido, nitro, and C₁ to C₄ alkoxy, with the proviso that when R₂is hydrogen or --OR₄ and R₄ is hydrogen, n is 0 or 1, or thepharmaceutically acceptable salts thereof.
 2. The R enantiomer of acompound according to claim
 1. 3. A compound according to claim 1wherein R₁ is hydrogen; R₂ is --(CH₂)_(m) --SO₂ R₈, --(CH₂)_(m) --SO₂R₈, --(CH₂)_(m) --(C═O)NHR₅, or --(CH₂)_(m) --NH(C═O)R₈ ; R₃ is hydrogenor methyl; and m, R₅ and R₈ are as defined in claim
 1. 4. A compoundaccording to claim 1, said compound being selectedfrom:(R)-5-methoxy-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole;(R)-5-bromo-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole(R)-5-(2-ethylsulfonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole;[(R)-5-(2-methylaminosulfonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole;(R)-5-(methylaminosulfonylmethyl)-3-(pyrrolidin-2-ylmethyl)-1H-indole;(R)-5-(methylaminosulfonylmethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole;](R)-5-carboxamido-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole;(R)-5-(2-methylsulfonylethyl)-3-(N-methylpyrrolidin-2-yl-methyl)-1H-indole;(R)-5-(2-methylsulfonamidoethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole;(R)-5-(2-aminosulphonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole[(R)-5-(2-aminosulphonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole;(R)-5-(2-N,N-dimethylaminosulphonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole;](R)-5-(2-phenylsulphonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indolehemisuccinate;(R)-5-(2-ethylsulphonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indolehemisuccinate;(R)-5-(2-phenylsulphonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole;(R)-5-(3-benzenecarbonylaminoprop-1-enyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole;(R)-5-(2-(4-methylphenylsulphonyl)ethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole;(R)-5-(3-methylsulphonylaminoprop-1-enyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole;(R)-5-(2-ethylsulphonylethyl)-3-(N-2-propylpyrrolidin-2-ylmethyl)-1H-indole;and (R)-5-(2-ethylsulphonylethyl)-3-(pyrrolidin-2-ylmethyl)-1H-indole[;and(R)-7-Bromo-5-(methylaminosulfonylmethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole].5. A pharmaceutical composition for treating a condition selected fromhypertension, depression, anxiety, eating disorders, obesity, drugabuse, cluster headache, migraine, pain, and chronic paroxysmalhemicrania and headache associated with vascular disorders comprising anamount of a compound according to claim 1 effective in treating suchcondition and a pharmaceutically acceptable carrier.
 6. A pharmaceuticalcomposition for treating disorders arising from deficient serotonergicneurotransmission comprising an amount of a compound according to claim1 effective in treating such a disorder and a pharmaceuticallyacceptable carrier.
 7. A method for treating a condition selected fromhypertension, depression, anxiety, eating disorders, obesity, drugabuse, cluster headache, migraine, pain and chronic paroxysmalhemicrania and headache associated with vascular disorders comprisingadministering to a mammal requiring such treatment an amount of acompound according to claim 1 effective in treating such condition.
 8. Amethod for treating disorders arising from deficient serotonergicneurotransmission comprising administering to a mammal requiring suchtreatment an amount of a compound according to claim 1 effective intreating such a disorder.
 9. The compound5-(2-phenylsulphonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indoleor a pharmaceutically acceptable salt thereof.
 10. A compound accordingto claim 9, wherein the compound is(R)-5-(2-phenylsulphonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole.11. A pharmaceutical composition for treating a condition selected fromhypertension, depression, anxiety, eating disorders, obesity, drugabuse, cluster headache, migraine, pain, and chronic paroxysmalhemicrania and headache associated with vascular disorders comprising anamount of a compound according to claim 9 effective in treating suchcondition and a pharmaceutically acceptable carrier.
 12. Apharmaceutical composition for treating disorders arising from deficientserotonergic neurotransmission comprising an amount of a compoundaccording to claim 9 effective in treating such a disorder and apharmaceutically acceptable carrier.
 13. A method for treating acondition selected from hypertension, depression, anxiety, eatingdisorders, obesity, drug abuse, cluster headache, migraine, pain andchronic paroxysmal hemicrania and headache associated with vasculardisorders comprising administering to a mammal requiring such treatmentan amount of a compound according to claim 9 effective in treating suchcondition.
 14. A method for treating disorders arising from deficientserotonergic neurotransmission comprising administering to a mammalrequiring such treatment an amount of a compound according to claim 9effective in treating such a disorder.
 15. A pharmaceutical compositionfor treating a condition selected from hypertension, depression,anxiety, eating disorders, obesity, drug abuse, cluster headache,migraine, pain, and chronic paroxysmal hemicrania and headacheassociated with vascular disorders comprising an amount of a compoundaccording to claim 10 effective in treating such condition and apharmaceutically acceptable carrier.
 16. A pharmaceutical compositionfor treating disorders arising from deficient serotonergicneurotransmission comprising an amount of a compound according to claim10 effective in treating such a disorder and a pharmaceuticallyacceptable carrier.
 17. A method for treating a condition selected fromhypertension, depression, anxiety, eating disorders, obesity, drugabuse, cluster headache, migraine, pain and chronic paroxysmalhemicrania and headache associated with vascular disorders comprisingadministering to a mammal requiring such treatment an amount of acompound according to claim 10 effective in treating such condition. 18.A method for treating disorders arising from deficient serotonergicneurotransmission comprising administering to a mammal requiring suchtreatment an amount of a compound according to claim 10 effective intreating such a disorder.